This document summarizes research on the discovery of a novel class of orally active inhibitors of N-myristoyltransferase (NMT) that are trypanocidal, meaning they can kill the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT). Researchers screened over 63,000 compounds and identified a hit compound (1) that inhibited T. brucei NMT with low micromolar potency and also had activity against the parasite. They then optimized the hit through structure-activity relationship studies, improving potency against the enzyme and parasite as well as developing good oral pharmacokinetics. This led to a lead compound, DDD85646 (
This document summarizes a research article about Quality by Design (QbD), a systematic approach to pharmaceutical development that emphasizes product and process understanding based on sound science and quality risk management. Some key points:
1) QbD aims to develop robust processes to consistently deliver quality products by understanding critical quality attributes and controlling variables throughout the product lifecycle.
2) International guidelines like ICH Q8, Q9, and Q10 provide a framework for QbD implementation and its benefits like reduced regulatory oversight and manufacturing flexibility.
3) The QbD approach involves defining a quality target product profile, identifying critical quality attributes, understanding material and process impacts through risk assessment, and implementing a control strategy within
Examination Of Patent Applications In The Field Of Pharmaceuticals Patents| Draft Guidelines For Examination Of Patent Applications In The Field Of Pharmaceuticals issued by Indian Patent Office
Draft Guidelines for Examination of Patent Applications in the Field of Pharmaceuticals are made available to the public by the Indian Patent Office. The said guidelines are intended to bring in uniform practice for the examination of applications related to relevant pharmaceutical subject matter.
Knowledge-based chemical fragment analysis in protein binding sitesCresset
This document discusses an approach to selecting likely binding molecules for a protein target based on analyzing known protein-ligand interactions from the Protein Data Bank (PDB). It describes extracting "fragments" from ligands that form hydrogen bonds to common amino acids like Aspartic acid, Glutamic acid, Arginine, and Histidine. These fragments are analyzed to determine common structural motifs that preferentially interact with certain amino acid side chains. This knowledge could help medicinal chemists design new compounds likely to bind a given protein binding site.
Assay Virtual Screening Compounds for the Inhibitory Potencies against BACE 1Ben Leong
This document describes a study conducted by three students to assay virtual screening compounds for their inhibitory potencies against BACE1, the enzyme involved in the production of amyloid beta peptides in Alzheimer's disease. Ten organic chemical compounds were tested for their half-maximal inhibitory concentration (IC50) values against BACE1 using a fluorescence resonance energy transfer assay. Compounds were then tested for toxicity on SH-SY5Y human neuroblastoma cells using the MTT assay. Six compounds showed potent micro-molar inhibition of BACE1, and some exhibited low cytotoxicity. Compound 7 had an IC50 of 4.49 μM against BACE1 and was not toxic to SH-SY5Y cells even at 10 μM
This document is an assignment cover sheet for a student named Muhammad Zeeshan Ahmed for an assignment on organic solvents. It includes his student ID number, the assignment name, and due date. At the bottom is a declaration stating that the work is his own and has not been plagiarized. The accompanying document discusses various organic solvents like benzene, toluene, methanol, ethanol, and their properties, structures, and common uses.
EUGM15 - Zoltán Simon (Printnet): Drug Profile Matching - Drug Discovery by P...ChemAxon
Most drugs exert their effects via multi-target interactions, as hypothesized by polypharmacology. Here we introduce Drug Profile Matching (DPM) which is able to relate complex drug-protein interaction profiles with effect and target profiles. Structural data and registered effect profiles of all small-molecule drugs were collected and interactions to a series of non-target protein binding sites of each drug were calculated. Statistical analyses confirmed close relationships between the studied 177 effect and 77 target categories and the in silico generated interaction profiles of cca. 1,200 FDA-approved small-molecule drugs. Receiver Operating Characteristic analysis and 10-fold cross-validation was performed to assess the accuracy and robustness of the method. Based on the found relationships, the effect and target profiles of drugs can be revealed in their entirety, and hitherto uncovered effects and targets can be predicted in a systematic manner.
In order to investigate the predictive power of DPM, four effect categories (PPAR agonist, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor and dopamine agent) were selected and predictions in the set of the FDA-approved small-molecule drugs were verified by literature analysis and experimental tests.
Moreover, a large set consisting of 600,000 druglike molecules was selected from a database of 50 million compounds and their interaction profiles were generated. Based on these profiles and chemical similarity considerations, predictions were calculated and tested experimentally to find new candidates that are chemically dissimilar to the reference drugs.
EUGM 2013 - Ian Berry, Bob Marmon (Evotec): Classification and analysis of 21...ChemAxon
We will discuss how we classified and calculated properties for over 21 million commercially available compounds using a variety of ChemAxon and in-house tools (and aggregated properties). We will show a summary of the analysis of the data and show how we will use that to build better virtual screens.
This document summarizes research on the discovery of a novel class of orally active inhibitors of N-myristoyltransferase (NMT) that are trypanocidal, meaning they can kill the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT). Researchers screened over 63,000 compounds and identified a hit compound (1) that inhibited T. brucei NMT with low micromolar potency and also had activity against the parasite. They then optimized the hit through structure-activity relationship studies, improving potency against the enzyme and parasite as well as developing good oral pharmacokinetics. This led to a lead compound, DDD85646 (
This document summarizes a research article about Quality by Design (QbD), a systematic approach to pharmaceutical development that emphasizes product and process understanding based on sound science and quality risk management. Some key points:
1) QbD aims to develop robust processes to consistently deliver quality products by understanding critical quality attributes and controlling variables throughout the product lifecycle.
2) International guidelines like ICH Q8, Q9, and Q10 provide a framework for QbD implementation and its benefits like reduced regulatory oversight and manufacturing flexibility.
3) The QbD approach involves defining a quality target product profile, identifying critical quality attributes, understanding material and process impacts through risk assessment, and implementing a control strategy within
Examination Of Patent Applications In The Field Of Pharmaceuticals Patents| Draft Guidelines For Examination Of Patent Applications In The Field Of Pharmaceuticals issued by Indian Patent Office
Draft Guidelines for Examination of Patent Applications in the Field of Pharmaceuticals are made available to the public by the Indian Patent Office. The said guidelines are intended to bring in uniform practice for the examination of applications related to relevant pharmaceutical subject matter.
Knowledge-based chemical fragment analysis in protein binding sitesCresset
This document discusses an approach to selecting likely binding molecules for a protein target based on analyzing known protein-ligand interactions from the Protein Data Bank (PDB). It describes extracting "fragments" from ligands that form hydrogen bonds to common amino acids like Aspartic acid, Glutamic acid, Arginine, and Histidine. These fragments are analyzed to determine common structural motifs that preferentially interact with certain amino acid side chains. This knowledge could help medicinal chemists design new compounds likely to bind a given protein binding site.
Assay Virtual Screening Compounds for the Inhibitory Potencies against BACE 1Ben Leong
This document describes a study conducted by three students to assay virtual screening compounds for their inhibitory potencies against BACE1, the enzyme involved in the production of amyloid beta peptides in Alzheimer's disease. Ten organic chemical compounds were tested for their half-maximal inhibitory concentration (IC50) values against BACE1 using a fluorescence resonance energy transfer assay. Compounds were then tested for toxicity on SH-SY5Y human neuroblastoma cells using the MTT assay. Six compounds showed potent micro-molar inhibition of BACE1, and some exhibited low cytotoxicity. Compound 7 had an IC50 of 4.49 μM against BACE1 and was not toxic to SH-SY5Y cells even at 10 μM
This document is an assignment cover sheet for a student named Muhammad Zeeshan Ahmed for an assignment on organic solvents. It includes his student ID number, the assignment name, and due date. At the bottom is a declaration stating that the work is his own and has not been plagiarized. The accompanying document discusses various organic solvents like benzene, toluene, methanol, ethanol, and their properties, structures, and common uses.
EUGM15 - Zoltán Simon (Printnet): Drug Profile Matching - Drug Discovery by P...ChemAxon
Most drugs exert their effects via multi-target interactions, as hypothesized by polypharmacology. Here we introduce Drug Profile Matching (DPM) which is able to relate complex drug-protein interaction profiles with effect and target profiles. Structural data and registered effect profiles of all small-molecule drugs were collected and interactions to a series of non-target protein binding sites of each drug were calculated. Statistical analyses confirmed close relationships between the studied 177 effect and 77 target categories and the in silico generated interaction profiles of cca. 1,200 FDA-approved small-molecule drugs. Receiver Operating Characteristic analysis and 10-fold cross-validation was performed to assess the accuracy and robustness of the method. Based on the found relationships, the effect and target profiles of drugs can be revealed in their entirety, and hitherto uncovered effects and targets can be predicted in a systematic manner.
In order to investigate the predictive power of DPM, four effect categories (PPAR agonist, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor and dopamine agent) were selected and predictions in the set of the FDA-approved small-molecule drugs were verified by literature analysis and experimental tests.
Moreover, a large set consisting of 600,000 druglike molecules was selected from a database of 50 million compounds and their interaction profiles were generated. Based on these profiles and chemical similarity considerations, predictions were calculated and tested experimentally to find new candidates that are chemically dissimilar to the reference drugs.
EUGM 2013 - Ian Berry, Bob Marmon (Evotec): Classification and analysis of 21...ChemAxon
We will discuss how we classified and calculated properties for over 21 million commercially available compounds using a variety of ChemAxon and in-house tools (and aggregated properties). We will show a summary of the analysis of the data and show how we will use that to build better virtual screens.
We introduce ChemAxon Plexus, a new web application that integrates ChemAxon’s discovery tools into a clean and user friendly desktop tool for chemists. Launch features focus on compound library design and the tools supporting this; database management, chemical searching, library enumeration, phys-chem property calculation, virtual synthesis and similarity searching. We describe the integration of existing products, and a fresh take on their user interfaces to make them easier to use while keeping the essence and utility intact. We demo Plexus and its simplified Markush structure editor, a user interface for virtual screening and how effortless reaction setup can be.
Sandrogreco Sigma And Pi Electron Delocalization Focus On Substituent EffectsProfª Cristiana Passinato
This document provides a review of sigma- and pi-electron delocalization with a focus on substituent effects. It discusses the historical development of understanding substituent effects beginning with Louis Plack Hammett's introduction of substituent constants to quantitatively describe these effects. The review covers how sigma- and pi-electron delocalization are considered in relation to substituent effects, how these effects induce pi-electron delocalization, and how aromaticity relates to pi-electron delocalization. Methods for measuring pi-electron delocalization and relating sigma- and pi-electron delocalization to descriptors of substituent effects are also discussed.
Structural and biochemical studies of cold shock domain containing proteins.
This thesis examines cold shock domain containing proteins through three chapters:
[1] A novel DNA microarray approach is developed to determine the sequence specificity of single-stranded nucleic acid binding proteins. Using this method, the major cold shock protein CspB from Bacillus subtilis is shown to bind preferentially to pyrimidine-rich sequences, with a high affinity for the consensus sequence 5'-GTCTTTG/T-3'.
[2] Six cold shock proteins from Salmonella typhimurium (CspA, B, C, D, E, and H) are cloned, expressed, and purified.
Fragments for drug discovery and chemical biologywarwick_amr
This document discusses fragment-based drug discovery and chemical biology. It begins with an overview of using fragments to find small molecule hits that bind to targets, and the challenges of progressing those hits into drug leads. It provides examples of developing the Hsp90 inhibitor AUY922 from a fragment hit. It also discusses using fragments to explore new binding sites on the TolB protein and discover fragment-based enzyme activators of the glycoside hydrolase BtGH84.
The document summarizes the principles of drug discovery, including the following key points:
1) Drug discovery is a lengthy, expensive, and inefficient process involving target identification, screening, preclinical testing, and clinical trials that can take over 10 years from initial compound to approved drug.
2) Natural products, especially from plants, microbes, and marine organisms, have historically been an important source of leads for drug discovery due to their chemical diversity.
3) The modern drug discovery process involves high-throughput screening of large libraries of synthetic compounds and natural products to identify initial hits, which are then optimized in the hit-to-lead phase through medicinal chemistry and further testing.
Pyrimidine is a heterocycle that is the building block of many natural compounds including those found in RNA, DNA, antibiotics, and vitamins. It is resistant to electrophilic substitution reactions due to the electron deficient nature of its 2, 4, 6 positions. However, reactions can occur at the 5 position if an electron donating group is present. Pyrimidine undergoes nucleophilic addition reactions easily at its 2, 4, 6 positions and with oxidizing agents can form pyridine N-oxides, especially if an alkyl group is present. It is also synthesized through reactions with malonic esters, amidines, and from dichloropyrimidines. Many anticancer and antiviral
This lecture outlines the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound in drug discovery.
The document describes several reactions involving conjugate additions and discusses the stereochemical outcomes. It rationalizes the stereoselectivity using concepts like chair conformations, Felkin-Anh control, and Cram chelation control. By analyzing the transition states and preferred conformations, it is able to explain why the reactions favor one stereoisomer over another in each case.
The document discusses various topics related to chirality and stereochemistry including:
- Different forms that can exhibit chirality beyond just tetrahedral stereocenters.
- The relationship between enantiomers, diastereomers, and meso compounds for molecules with multiple stereocenters.
- How purity of chiral compounds is measured in terms of enantiomeric excess and ratio, and diastereomeric excess and ratio.
- Common methods for determining enantiomeric excess such as derivatization reactions and chiral chromatography.
This chapter discusses carbocations, which are positively charged carbon-containing ions that are highly reactive intermediates in organic chemistry. Carbocations have six electrons in the outer shell of the central carbon atom. They are stabilized by electron-donating groups and destabilized by electron-withdrawing groups. Carbocations undergo various reactions including reactions with nucleophiles, elimination reactions, rearrangement reactions, and additions to unsaturated systems. Non-classical carbocations are also discussed.
Markush Claims: Representation, Search, Analysis and Construction - Where Are...Dr. Haxel Consult
Markush claims are widely used in chemical patents to define large chemical spaces, however understanding these structures, their formalized representation, search and analysis is complex and poorly supported. The problem becomes more acute with the need for comparison of these potentially vast patent Markush structures with classic structure and combinatorial virtual libraries. At this time, all of the existing Markush representations are incomplete, search systems are proprietary and not available for in-house integration and with many key use cases there are no existing tools and often no algorithmic background to begin the solve. This presentation briefly summarizes the current state of Markush claims, the existing challenges from the perspective of both IP professionals and computational chemists and highlights some promising new developments directly relevant to today's discovery processes.
COMPREHENSIVE HANDOUT FOR ORGANIC CHEMISTRYPaolo Naguit
This document provides an overview of organic chemistry nomenclature and structural formulas. It discusses the different types of structural formulas used to depict organic molecule structures, including straight-line, condensed, 3D, and skeletal formulas. It also outlines the IUPAC rules for systematic nomenclature, including naming conventions for functional groups, prefixes, parents, locants, and suffixes. Key aspects covered include priority rules for determining the parent chain and functional group that occupies the suffix. Functional groups are organized by priority in a table with their corresponding prefixes and suffixes. Naming conventions are also discussed for classes of organic compounds including alkanes, alkyl halides, alkenes and alkynes.
This document provides an introduction to carboxylic acids and their derivatives. It discusses the abundance and uses of carboxylic acids in nature and industry. Key topics covered include the nomenclature of carboxylic acids, the structure and properties that result from the carboxylic acid functional group, such as acidity and hydrogen bonding. Methods of preparing and reacting carboxylic acids are also summarized, along with an introduction to common carboxylic acid derivatives like esters, acid halides, anhydrides, and amides.
A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.
2006 a space oddity – the great pluto debate science _ the guardianGeorgi Daskalov
Long known as the ninth planet, Pluto was downgraded in 2006, sparking a scientific spat that raises basic questions about how we understand the universe
The document discusses Google tools that can be used to find relevant consumer insights for RFPs, creative briefs, and content strategies. It describes YouTube Analytics, Google Consumer Surveys, Google Trends, Google Correlate, which can provide fast focus group data, test consumer insights, uncover growing and declining interests, and find related search trends. These tools allow accessing larger samples of data faster and more cost-effectively than traditional market research methods to better inform marketing strategies.
Getting cytisine licensed for use world-wide: a call to actionGeorgi Daskalov
Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised.
Evaluation of the efficacy and safety of tribulus terrestris in male sexual d...Georgi Daskalov
Evaluation of the efficacy and safety of tribulus terrestris in male sexual dysfunction – a prospective, randomized, double blinded, placebo controlled clinical trial 2015 poster
This document summarizes national trends in prescription drug expenditures in the United States for 2015 and provides projections for 2016. Key findings include:
- Total US prescription drug sales in 2015 were $419.4 billion, an 11.7% increase over 2014. Spending in clinics and non-federal hospitals increased 15.9% and 10.7%, respectively.
- Growth in overall spending was driven primarily by price increases for existing drugs (8.4%), with new drugs (2.7%) and changes in drug usage (0.5%) also contributing. Hospital spending growth was mainly from price increases, while clinic growth was mostly from increased drug usage.
- Projections estimate an 11-13%
This document discusses how pharmaceutical companies can improve clinical development and manufacturing processes through product lifecycle management (PLM). It identifies 7 key business processes for transforming R&D operations: 1) drug development program management, 2) regulatory archive management, 3) clinical trial management, 4) scale-up and commercial manufacturing, 5) quality management, 6) packaging and marketing asset management, and 7) global product registration. Implementing PLM using Oracle's solutions can deliver ROI by improving productivity, reducing time to market, and lowering development costs.
We introduce ChemAxon Plexus, a new web application that integrates ChemAxon’s discovery tools into a clean and user friendly desktop tool for chemists. Launch features focus on compound library design and the tools supporting this; database management, chemical searching, library enumeration, phys-chem property calculation, virtual synthesis and similarity searching. We describe the integration of existing products, and a fresh take on their user interfaces to make them easier to use while keeping the essence and utility intact. We demo Plexus and its simplified Markush structure editor, a user interface for virtual screening and how effortless reaction setup can be.
Sandrogreco Sigma And Pi Electron Delocalization Focus On Substituent EffectsProfª Cristiana Passinato
This document provides a review of sigma- and pi-electron delocalization with a focus on substituent effects. It discusses the historical development of understanding substituent effects beginning with Louis Plack Hammett's introduction of substituent constants to quantitatively describe these effects. The review covers how sigma- and pi-electron delocalization are considered in relation to substituent effects, how these effects induce pi-electron delocalization, and how aromaticity relates to pi-electron delocalization. Methods for measuring pi-electron delocalization and relating sigma- and pi-electron delocalization to descriptors of substituent effects are also discussed.
Structural and biochemical studies of cold shock domain containing proteins.
This thesis examines cold shock domain containing proteins through three chapters:
[1] A novel DNA microarray approach is developed to determine the sequence specificity of single-stranded nucleic acid binding proteins. Using this method, the major cold shock protein CspB from Bacillus subtilis is shown to bind preferentially to pyrimidine-rich sequences, with a high affinity for the consensus sequence 5'-GTCTTTG/T-3'.
[2] Six cold shock proteins from Salmonella typhimurium (CspA, B, C, D, E, and H) are cloned, expressed, and purified.
Fragments for drug discovery and chemical biologywarwick_amr
This document discusses fragment-based drug discovery and chemical biology. It begins with an overview of using fragments to find small molecule hits that bind to targets, and the challenges of progressing those hits into drug leads. It provides examples of developing the Hsp90 inhibitor AUY922 from a fragment hit. It also discusses using fragments to explore new binding sites on the TolB protein and discover fragment-based enzyme activators of the glycoside hydrolase BtGH84.
The document summarizes the principles of drug discovery, including the following key points:
1) Drug discovery is a lengthy, expensive, and inefficient process involving target identification, screening, preclinical testing, and clinical trials that can take over 10 years from initial compound to approved drug.
2) Natural products, especially from plants, microbes, and marine organisms, have historically been an important source of leads for drug discovery due to their chemical diversity.
3) The modern drug discovery process involves high-throughput screening of large libraries of synthetic compounds and natural products to identify initial hits, which are then optimized in the hit-to-lead phase through medicinal chemistry and further testing.
Pyrimidine is a heterocycle that is the building block of many natural compounds including those found in RNA, DNA, antibiotics, and vitamins. It is resistant to electrophilic substitution reactions due to the electron deficient nature of its 2, 4, 6 positions. However, reactions can occur at the 5 position if an electron donating group is present. Pyrimidine undergoes nucleophilic addition reactions easily at its 2, 4, 6 positions and with oxidizing agents can form pyridine N-oxides, especially if an alkyl group is present. It is also synthesized through reactions with malonic esters, amidines, and from dichloropyrimidines. Many anticancer and antiviral
This lecture outlines the different strategies for finding a fragment hit and the subsequent elaboration strategies used in order to increase potency to develop a lead compound in drug discovery.
The document describes several reactions involving conjugate additions and discusses the stereochemical outcomes. It rationalizes the stereoselectivity using concepts like chair conformations, Felkin-Anh control, and Cram chelation control. By analyzing the transition states and preferred conformations, it is able to explain why the reactions favor one stereoisomer over another in each case.
The document discusses various topics related to chirality and stereochemistry including:
- Different forms that can exhibit chirality beyond just tetrahedral stereocenters.
- The relationship between enantiomers, diastereomers, and meso compounds for molecules with multiple stereocenters.
- How purity of chiral compounds is measured in terms of enantiomeric excess and ratio, and diastereomeric excess and ratio.
- Common methods for determining enantiomeric excess such as derivatization reactions and chiral chromatography.
This chapter discusses carbocations, which are positively charged carbon-containing ions that are highly reactive intermediates in organic chemistry. Carbocations have six electrons in the outer shell of the central carbon atom. They are stabilized by electron-donating groups and destabilized by electron-withdrawing groups. Carbocations undergo various reactions including reactions with nucleophiles, elimination reactions, rearrangement reactions, and additions to unsaturated systems. Non-classical carbocations are also discussed.
Markush Claims: Representation, Search, Analysis and Construction - Where Are...Dr. Haxel Consult
Markush claims are widely used in chemical patents to define large chemical spaces, however understanding these structures, their formalized representation, search and analysis is complex and poorly supported. The problem becomes more acute with the need for comparison of these potentially vast patent Markush structures with classic structure and combinatorial virtual libraries. At this time, all of the existing Markush representations are incomplete, search systems are proprietary and not available for in-house integration and with many key use cases there are no existing tools and often no algorithmic background to begin the solve. This presentation briefly summarizes the current state of Markush claims, the existing challenges from the perspective of both IP professionals and computational chemists and highlights some promising new developments directly relevant to today's discovery processes.
COMPREHENSIVE HANDOUT FOR ORGANIC CHEMISTRYPaolo Naguit
This document provides an overview of organic chemistry nomenclature and structural formulas. It discusses the different types of structural formulas used to depict organic molecule structures, including straight-line, condensed, 3D, and skeletal formulas. It also outlines the IUPAC rules for systematic nomenclature, including naming conventions for functional groups, prefixes, parents, locants, and suffixes. Key aspects covered include priority rules for determining the parent chain and functional group that occupies the suffix. Functional groups are organized by priority in a table with their corresponding prefixes and suffixes. Naming conventions are also discussed for classes of organic compounds including alkanes, alkyl halides, alkenes and alkynes.
This document provides an introduction to carboxylic acids and their derivatives. It discusses the abundance and uses of carboxylic acids in nature and industry. Key topics covered include the nomenclature of carboxylic acids, the structure and properties that result from the carboxylic acid functional group, such as acidity and hydrogen bonding. Methods of preparing and reacting carboxylic acids are also summarized, along with an introduction to common carboxylic acid derivatives like esters, acid halides, anhydrides, and amides.
A look at epothilone A as it includes examples of many different forms of asymmetric synthesis. Also includes a little bit about ring-closing metathesis.
2006 a space oddity – the great pluto debate science _ the guardianGeorgi Daskalov
Long known as the ninth planet, Pluto was downgraded in 2006, sparking a scientific spat that raises basic questions about how we understand the universe
The document discusses Google tools that can be used to find relevant consumer insights for RFPs, creative briefs, and content strategies. It describes YouTube Analytics, Google Consumer Surveys, Google Trends, Google Correlate, which can provide fast focus group data, test consumer insights, uncover growing and declining interests, and find related search trends. These tools allow accessing larger samples of data faster and more cost-effectively than traditional market research methods to better inform marketing strategies.
Getting cytisine licensed for use world-wide: a call to actionGeorgi Daskalov
Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised.
Evaluation of the efficacy and safety of tribulus terrestris in male sexual d...Georgi Daskalov
Evaluation of the efficacy and safety of tribulus terrestris in male sexual dysfunction – a prospective, randomized, double blinded, placebo controlled clinical trial 2015 poster
This document summarizes national trends in prescription drug expenditures in the United States for 2015 and provides projections for 2016. Key findings include:
- Total US prescription drug sales in 2015 were $419.4 billion, an 11.7% increase over 2014. Spending in clinics and non-federal hospitals increased 15.9% and 10.7%, respectively.
- Growth in overall spending was driven primarily by price increases for existing drugs (8.4%), with new drugs (2.7%) and changes in drug usage (0.5%) also contributing. Hospital spending growth was mainly from price increases, while clinic growth was mostly from increased drug usage.
- Projections estimate an 11-13%
This document discusses how pharmaceutical companies can improve clinical development and manufacturing processes through product lifecycle management (PLM). It identifies 7 key business processes for transforming R&D operations: 1) drug development program management, 2) regulatory archive management, 3) clinical trial management, 4) scale-up and commercial manufacturing, 5) quality management, 6) packaging and marketing asset management, and 7) global product registration. Implementing PLM using Oracle's solutions can deliver ROI by improving productivity, reducing time to market, and lowering development costs.
This document discusses the therapeutic index of antihistamines, which is defined as the benefit-to-risk ratio or efficacy-to-safety ratio that determines the range of doses where a drug is effective and safe. While second-generation antihistamines have similar efficacy for allergic rhinitis and urticaria, they differ in their safety profiles and therapeutic indices. Fexofenadine has one of the broadest therapeutic indices, having been shown to be effective at doses as low as 20 mg twice daily and not causing sedation or cardiac toxicity at doses as high as 690 mg twice daily. A broad therapeutic index is important considering potential drug interactions and situations where patients increase their dose in search of
Extreme trans neptunian objects and the kozai mechanismGeorgi Daskalov
This document summarizes a study examining the possibility of undiscovered planets beyond Neptune based on the discovery of extreme trans-Neptunian objects (ETNOs). The study finds:
1) There is an observational bias that most ETNOs would be discovered at declinations of -24 to 24 degrees, regardless of survey completeness.
2) The clustering of the arguments of perihelion of known ETNOs near 0 degrees cannot be explained by observational biases and suggests the influence of an unseen planetary perturber.
3) The distributions of orbital parameters of known ETNOs show clustering that resembles mean motion resonances and families influenced by planetary perturbations, providing further evidence for one or more undis
Some In Vitro/In Vivo Chemically-Induced Experimental Models of Liver Oxidati...Georgi Daskalov
This review article summarizes several experimental models used to study liver oxidative stress and injury in rats, including those induced by carbon tetrachloride, tert-butyl hydroperoxide, ethanol, paracetamol, and nicotine. The models are described as involving the generation of reactive oxygen species that cause lipid peroxidation, glutathione depletion, and damage to cellular proteins and DNA, leading to effects like increased membrane permeability and cell death. Specifically, the models examine how these compounds are metabolized to produce radicals that can induce oxidative stress in the liver and hepatocytes.
This document provides information and instructions for EEA-qualified pharmacists applying for recognition as a pharmacist in Great Britain by the General Pharmaceutical Council (GPhC). The GPhC is the regulatory body that oversees pharmacists and pharmacy technicians in Great Britain. Applicants must submit documentation including proof of qualifications, identity, nationality, registration status in their home country, and fees. Required documents include diplomas, licenses, passport, birth certificate, marriage certificate if applicable, police records, and letters from authorities confirming standing and compliance with EU directives. Photographs must be certified by a professional acquaintance. All documents may require certified English translations. The process is expected to take one month, after which eligible applicants will receive a
Pharmaceutical marketing to healthcare providers provides information on new treatment options, but it is only one of many factors that influence prescribing decisions. Surveys find clinical knowledge, patient factors, and insurance policies have greater impacts. Approximately 67% of US prescriptions are for generic drugs, much higher than other countries. While representatives provide information, prescribing is shaped more by clinical guidelines, peers, formularies, and insurers' prior authorization requirements than representative interactions.
Product lifecycle management in the pharmaceutical industryGeorgi Daskalov
Pharmaceutical companies face pressure to improve product pipelines, accelerate time to market, and improve margins on existing products, while maintaining strict regulatory compliance. A comprehensive product lifecycle management (PLM) solution can help address these challenges by providing visibility and control across the entire drug development process from discovery through commercialization. PLM focuses on leveraging research and development efforts to efficiently develop new drugs and move them through the various phases of the drug lifecycle from the different internal and external functions involved. This allows for improved collaboration and management of changes to optimize profitability throughout the drug's economic life.
The document discusses various topics related to economics, politics, and society around the world. It mentions different countries, currencies, trade agreements, and political leaders. It also references challenges and opportunities facing certain industries. However, most of the information is garbled or unclear due to the formatting and characters used.
The document discusses various topics related to economics, politics, and society around the world. It mentions different countries, currencies, trade agreements, and political leaders. It also references challenges and opportunities facing certain industries. However, most of the information is garbled or unclear due to the formatting issues.
Health-care interventions to promote and assist tobacco cessation: a review o...Georgi Daskalov
This document reviews the efficacy, effectiveness, and affordability of healthcare interventions for tobacco cessation. It finds that brief advice from healthcare workers can promote smoking cessation and is affordable globally. Telephone and text support programs and printed materials can assist with quit attempts and are globally affordable. Face-to-face behavioral support increases quit rates for cigarettes and smokeless tobacco and is affordable in middle- and high-income countries. Several medications can aid quitting when combined with behavioral support, with cytisine and nortriptyline being globally affordable. Brief advice, telephone/text support, self-help materials, cytisine, and nortriptyline are identified as globally affordable tobacco cessation interventions.
The document discusses regulations around access to and classification of medicines in the UK and Europe. It describes three categories of medicines in the UK - prescription only medicines (POM), pharmacy medicines (P), and general sales list medicines (GSL). POM medicines require a prescription, P medicines can only be sold under pharmacy supervision, and GSL medicines can be sold in any retail outlet. There has been a trend of increasing medicines moving from POM to P to GSL status, making them more accessible over the counter without a prescription. This deregulation aims to empower consumers, improve access, and reduce costs, but must balance this with safety and professional oversight.
Acute activation, desensitization and smoldering activation of human acetylch...Georgi Daskalov
This study examined the acute activation and chronic desensitization of human nicotinic acetylcholine receptors (AChRs) containing α4β2, α3β4, and α7 subunits by nicotine and other nicotinic agonists. It found that nicotine causes "smoldering activation" of α4β2 AChRs at concentrations found in smokers, but higher concentrations are needed for α3β4 and α7 AChRs. Sazetidine-A selectively activates and desensitizes the (α4β2)2β2 stoichiometry of the α4β2 AChR. The study defines the concentration ranges over which different agonists can sustain smolder
1. Diss. ETH Nt. 15220
Novelligands for the Neuronal nAChR:
Synthesis, in vitro Characterizations and
Binding Models
A dissertation submitted to the
Swiss Federal Institute ofTechnology Zurich
for the degree of
Doctor ofNatural Seiences
presented by
William H. Bisson
Laurea in Chimica
University of Padua, Italy
born April 28th
, 1974
citizen of Treviso, Italy
accepted on the recommendation of
Prof. Dr. P.A. Schubiger, examiner
Prof. Dr. G. Folkers, co-examiner
Dr. G. Westera, co-examiner
2003
2. VI
SUMMARY
The present projeet is aimed at the design and development of non-toxic ligands with
speeifieity and subtype seleetivity towards the neuronal nAChRs. The potential benefit
of nieotinie ligands for a variety of neurodegenerative diseases (like AD), due to the
involvement of nAChRs in eognitive processes, has energised research efforts in this
direetion.
The naturalligands (-)-epibatidine and (-)-eytisine proved to exhibit high affmity and
agonism aetivity towards neuronal nAChRs but their clinieal use, eause of their
toxicity, is precluded.
(-)-epibatidine
CI
(- )-cytisine
Aseries of epibatidine and eytisine derivatives were synthesised and investigated by in
vitro binding and eleetrophysiology studies. This permitted to put into eorrelation the
ligand ehemieal strueture and the affmity and biological response towards different
nAChR subtypes.
Binding-experiments on the two most present subtypes in the brain, were performed
using the eompetition assay with eH]-cytisine (U4ß2 nAChR) and e25
I]-alpha-
bungarotoxin (U7 nAChR) as radioligands.
Voltage clamp eleetrophysiology was perfonned on neuronal (U4ß2 and (7) and
ganglionie (U3ß4) nAChRs reeonstituted inXenopus ooeytes.
All compounds showed, by binding studies, low affinity towards the U7 neuronal
nieotinie reeeptor and mueh higher affmity for the U4ß2 subtype, whieh indieates high
seleetivity towards the U4ß2 neuronal subtype.
3. VII
The affinity for a4ßZ neuronal nicotinic receptor is related to thechemical structure of
the ligand. All compounds synthesised possess the three geometrically independent
pharmacophoric structural features requested for binding recently mentioned by
Nicolotti et al. Nevertheless the affinity obtained varied a lot among the compounds
studied. Bromocytisine showed the highest affinity (K = 0.153 uM) towards the U4ßz
subtype but low subtype selectivity due to its full agonism towards the ganglionic a3ß4
subtype receptor. Compound (±)-33bMet, shown below, exhibited high affmity (K, = 2
uM) and partial agonism for the a4ßZ subtype but significant subtype selectivity too,
N/
Compound (±)-33bMet was then injected intravenously into mice and was proved to
be relatively non-toxic with a median lethai dose of> 0.5 mg/kg mouse body weight.
All the binding, electrophysiology and toxicology data found make compound (±)-
33bMet to be a potential radiotracer for in vivo brain PET investigations.
Recently the crystalline structure of the acetylcholine-binding protein (AChBP),
isolated from snails, has been resolved. It is a soluble homopentamer protein revealing
in the binding site region high homology with the extracellular N-terminal domain of
different species nAChR subunits. This would give then the possibility to model some
ofthe existing nAChR subtypes.
In the present work the homology-models of the extracellular domain of the rat and
human neuronal (U4ßz) and (U7) and ofthe rat ganglionic (U3ß4) nAChR subtypes were
built, energetically minimized and their stability was assessed using molecular
dynamies.
Aseries of nicotinic ligands were docked into the binding cavity of the non-
dynamicised rat U4ßz and U3ß4 subtypes to investigate the relationship between
structure and affinity and between structure and subtype selectivity, which is probably
connected to toxic side effects.
4. vrn
The docking in both modeled subtypes confirmed, for the protein-ligand complex, the
importance of cation-z interactions between the quatemary positive nitrogen of the
ligand and the aromatic pocket in the binding site region and the hydrogen bond
between a hydrogen acceptor in the ligand and a hydrogen donor of a residue present
in the receptor binding site.
In the rat U4ß2 subtype two doeking orientations (clusters 1 shown in the Figure below
and 2), with the highest consensus score, were identified involving high affmity
ligands like epibatidine, dechloroepibatidine and (S)-A-85380. The doeking
orientations clusters 1 and 2 are preferred respeetively by clinieally toxic and non-toxic
ligands, which tumed to be an interesting result.
All ligands studied didn't dock weIl into the U3ß4 model with the exception of
epibatidine, dechloroepibatidine, (±)-33bMet and the Abbott derivative (S)-A-98795.
The docking data obtained reveal that the presence of the oxygen atom between the
pyridine ring and the aliphatic moiety plays an important role in the U4ß2 subtype
selectivity and that the flexibility eonstrietion around the ligand C-O-C and C-C-C
angles increases affmity towards the U3ß4 eavity.
These doeking investigations showed that the studied nieotinic models are useful for
structure-based design of speeific and selective U4ß2 nAChR subtype ligands for
therapeutie and diagnostie applieations in neurological diseases.
5. IX
ZUSA~NFASSUNG
Das vorliegende Projekt hat zum Ziel, nicht-toxische Liganden zu entwerfen und zu
entwickeln, die Spezifität und Subtyp-Selektivität gegenüber neuronalen nAChRs
aufweisen. Der potentielle Nutzen von nicotinischen Liganden für eine Vielfalt von
neurodegenerativen Erkrankungen (wie beispielsweise der Alzheimer-Krankheit),
herrührend durch die Beteiligung von nAChRs in kognitiven Prozessen, hat die
Forschung auf diesem Gebiet angetrieben.
Die natürlichen Liganden (-)-Epibatidin und (-)-Cytisin wiesen eine hohe Affinität
sowie agonistische Aktivität gegenüber neuronalen nAChRs auf, deren klinischer
Gebrauch ist jedoch wegen deren Toxizität ausgeschlossen.
(- )-epibatidine
CI
o
(- )-cytisine
Darauffolgend wurde eine Reihe von Epibatidin- und Cytisinderivaten synthetisiert
und in vitro mit Hilfe von Bindungs- und elektrophysiologischen Studien untersucht.
Dies erlaubte, die chemische Ligandstruktur, die Affinität und die biologische Antwort
auf verschiedene nAChR-Subtypen in Zusammenhang zu bringen. Bindungsstudien
der beiden am häufigsten vorkommenden Subtypen im Gehirn wurden unter
Anwendung des Competition Assays mit eH]-Cytisin (C4ß2 nAChR) und C25
I]-alpha-
bungarotoxin (0.7 nAChR) als Radoliganden durchgefiihrt. Des weiteren wurden
Voltage-clamp-Elektrophysiologiestudien an neuronalen (f4ß2 und 0.7) und
ganglionären (U3ß4) nAChR von Xenopus Oocyten vorgenommen.
Alle Verbindungen zeigten in den Bindungsstudien niedrige Affmität gegenüber des
neuronalen u7-nikotinischen Rezeptors, aber weit höhere Affinität gegenüber dem
6. x
neuronalen u3ß4-Subtyp, was für eine hohe Selektivität des neuronalen U4ß2-Subtyps
spricht.
Die Affmität gegenüber dem neuronalen U4ßrnikotinischen Rezeptor steht in
Verbindung mit der chemischen Struktur des Liganden. Alle synthetisierten
Verbindungen besitzen die drei geometrischen, voneinander unabhängigen
pharmakophoren Strukturmerkmale, welche für die Bindung notwendig sind und die
kürzlich von Nicolotti et al erwähnt wurden. Allerdings variierten die erhaltenen
Affinitäten stark bei den betrachteten Verbindungen.
Bromocytisin zeigte die höchste Affinität (K, = 0.153 nM) gegenüber dem U4ß2-
Subtyp, jedoch geringe Subtyp-Selektivität wegen seines Agonismus gegenüber dem
ganglionären u3ß4-Subtyp-Rezeptor. Verbindung (±)-33bMet, wie unten gezeigt, wies
gegenüber dem u3ß4-Subtyp hohe Affinität (K, = 2 nM) und partiellen Agonismus
sowie signifikante Subtyp-Selektivität auf.
N/
Verbindung (±)-33bMet wurde im Anschluss daran intravenös in Mäuse injiziert und
erwies sich als relativ untoxisch mit einer mittleren letalen Dosis von >0.5 mg/kg
Maus-Körpergewicht.
Alle gefundenen Bindungs-, E1ektrophysiologie- und Toxiziätsdaten belegen, dass
Verbindung (±)-33bMet ein potentieller Radiotracer für in vivo PET-Untersuchungen
am Gehirn ist.
Kürzlich wurde die Kristallstruktur des Acety1cholin-Bindeproteins (AChBP), isoliert
aus Schnecken, entschlüsselt. Es handelt sich um ein lösliches, homopentameres
Protein, welches in seiner Bindungsseite eine hohe Homologie mit der extrazellulären,
N-terminalen Domäne der nAChR-Untereinheiten verschiedener Spezies aufweist.
Dies würde gegebenenfalls ermöglichen, einige der im Körper existierenden nAChR-
Subtypen zu modellieren.
7. XI
In der vorliegenden Arbeit wurden demzufolge Homologie-Modelle der
extrazellulären Domäne der ganglionären (U3ß4)-nAChR-Subtypen in der Ratte und der
neuronalen (<l4ß2)- und (u7)-nAChR-Subtypen der Ratte und des Menschen erstellt,
energetisch minimiert und ihre Stabilität mit Hilfe von molekularer Dynamik geprüft.
Eine Reihe nikotinischer Liganden wurden in die Bindungstasche der nicht-
dynamisierten <l4ß2- und U3ß4-Subtypen der Ratte eingepasst, um die Beziehung
zwischen Struktur und Affmität sowie zwischen Struktur und Subtyp-Spezifität zu
studieren, welche möglicherweise mit toxischen Nebeneffekten in Verbindung steht.
Das Docking in beiden modellierten Subtypen bekräftigte für den Protein-Ligand-
Komplex die Wichtigkeit der Kationen-x-Interaktionen zwischen dem quaternären
positiven Stickstoffatom des Liganden und der aromatischen Tasche in der
Bindungsregion und der Wasserstoflbrücke zwischen einem Wasserstoff-Akzeptor im
Liganden und einem Wasserstoff-Donor emer Amionsäure, die m der
Rezeptorbindungsstelle vorhanden ist. Im <l4ßrSubtyp der Ratte wurden zwei
Docking-Orientierungen (Cluster 1 und 2) mit dem höchsten Consensus Score
identifiziert, die hochaffine Liganden wie Epibatidin, Dechloroepibatidin und (S)-A-
85380 miteinbeziehen. Die Docking-Orientierung Cluster 1 wird von klinisch
toxischen und die Docking-Orientierung Cluster 2 von nicht-toxischen Liganden
bevorzugt, was sich als interessantes Resultat herausstellte.
Alle der studierten Liganden dockten nicht gut ans u3ß4-Modell mit Ausnahme von
Epibatidin, Dechloroepibatidin, (±)-33bMet und vom Abbott Derivat (S)-A-98795. Die
erhaltenen Docking-Daten zeigen, dass die Anwesenheit vom Sauerstoffatom zwischen
dem Pyridin-Ring und dem aliphatischen Teil eine wichtige Rolle in der U4ßrSubtyp
Selektivität spielt und dass die Flexibiltätseinschränkung um die C-O-C- und C-C-C-
Winkel des Liganden die Affinität gegenüber der U3ß4-Tasche erhöht.
Diese Docking-Untersuchungen zeigten, dass die untersuchten nicotinischen Modelle
hilfreich für Struktur-basiertes Design von spezifischen und selektiven <l4ß2-nAChR-
Subtyp Liganden sind, die für therapeutische und diagnostische Zwecke bei
neurologischen Erkrankungen Anwendung finden.