Diese Präsentation wurde erfolgreich gemeldet.
Die SlideShare-Präsentation wird heruntergeladen. ×

Natural products in drug discovery

Wird geladen in …3

Hier ansehen

1 von 36 Anzeige

Weitere Verwandte Inhalte

Diashows für Sie (20)

Ähnlich wie Natural products in drug discovery (20)


Aktuellste (20)

Natural products in drug discovery

  1. 1. Natural Products in Drug Discovery Dr. G. Sakthivel
  2. 2. What is Drug? A chemical substances administered to the person or animal to cure disease. Webster’s Dictionary…. An agent intended diagnose, switch ON or OF certain enzymatic action, treat cure or prevent diseases in human or other animals. Expanded definition….
  3. 3. What is? Drug Discovery & Drug Design Drug discovery includes: • Concept • Mechanism • Serious biological assay • Screening hit identification • In-vivo proof of concept in animals and therapeutic index Development begins when the decision is made to put a molecule into Phase I clinical trials Mandal et al., "Rational drug design."European journal of pharmacology 625.1 (2009): 90-100.
  4. 4. Drug design includes: • Development of small molecules with desired properties for targets, biomolecules (proteins or nucleic acids), • whose functional roles in cellular processes and 3D structural information are known. • This approaching drug design is well established and • Is being applied extensively by the pharmaceutical industries. • Development of small molecules with predefined properties for targets (whose cellular functions and their structural information may be known or unknown. • Knowledge of unknown targets (genes and proteins) can be obtained by analyzing data bases using advanced computational tools. Mandal et al., "Rational drug design."European journal of pharmacology 625.1 (2009): 90-100.
  5. 5. Characteristics of Drugs: • Molecular weight and size • Structure-activity relationship • Solubility • Dosage form • Should maintain the half life time • It will not produce any toxicity or side effects • Affinity to bind with target or plasma proteins or receptors. • Should not affect the other enzymatic or physiological function. epharmacology.hubpages.com/hub/Characteristics-of-Drug
  6. 6. Drug Discovery & Development Process Identify disease Isolate protein involved in disease (2-5 years) Find a drug effective against disease protein (2-5 years) Preclinical testing (1-3 years) Formulation Human clinical trials (2-10 years) Scale-up Approval (2-3 years)
  7. 7. THE DISCOVERY PROCESS Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Pre-discovery Target identification Target validation Lead identification & optimization Preclinical testing Development Process (Phase I, II & II)
  8. 8. THE DISCOVERY PROCESS Step 1 Pre-discovery Understand the disease • Before any potential new medicine can be discovered, First work to understand the disease to be treated as well as possible. • They try to understand how the genes are altered. • how that affects the proteins they encode and how those proteins interact with each other in living cells. • How those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. • This knowledge is the basis for treating the problem.
  9. 9. THE DISCOVERY PROCESS Step 2 Target identification Choose a molecule to target with a drug • A target is generally a single molecule, such as a gene or protein, which is involved in a particular disease. • Even at this early stage in drug discovery it is critical that researchers pick a target that is “drug able” • i.e., one that can potentially interact with and be affected by a drug molecule. DNA, Protein or Enzyme
  10. 10. THE DISCOVERY PROCESS Step 3 Target validation Test the target and confirm its role in the disease • Demon-strate that a particular target is relevant to the disease being studied through complicated experiments in both living cells and in animal models of disease .
  11. 11. THE DISCOVERY PROCESS Step 4 Lead identification & optimization There are a few ways to find a lead compound Mother Nature: • Until recently, scientists usually turned to nature to find interesting compounds for fighting disease.
  12. 12. sources Microbial World Animal Sources Marine World Venom & Toxins Plant Kingdom
  13. 13. THE DISCOVERY PROCESS Step 4 Lead identification & optimization There are a few ways to find a lead compound Mother Nature: • Until recently, scientists usually turned to nature to find interesting compounds for fighting disease. Mother nature still offers many useful substances, but now there are other ways to approach drug discovery . • De novo • High-throughput Screening
  14. 14. THE DISCOVERY PROCESS Lead optimization • Lead compounds go through a series of tests to provide an early assessment of the safety of the lead compound. • Test include Absorption • Distribution • Metabolism • Excretion and Toxicological (ADME/Tox) properties. Step 4 Lead identification & optimization Early Safety Tests:
  15. 15. Venom & Toxin Based Drug Discovery Approach Basic Work Flow • Characterization of venom: MALDI-TOF Mass spectrometry • Isolate and purification of toxin peptides from venom Gel electrophoresis and Chromatography techniques like reverse-phase HPLC • Sequencing and structure determination of isolated peptides. Liquid phase sequencer and Automated sequencing method. Mass Spectrometry, NMR and X-ray Crystallography for structure predication. • Invivo and Invitro study for the activity of isolated major peptides. Explore the pharmacological and systematic function of the toxin. • Computational & system biology approach Computational biological & system approach will be implemented to calculate the accurate binding pathway and target the structural function of the peptides with the target membrane receptors
  16. 16. THE DISCOVERY PROCESS Step 5 Preclinical testing • Lab and animal testing to determine if the drug is safe enough for human testing
  17. 17. Important Points in Drug Design based on Bioinformatics Tools • Chemical Modification of Known Drugs – Drug improvement by chemical modification – Pencillin G -> Methicillin; morphine->nalorphine • Receptor Based drug design – Receptor is the target (usually a protein) – Drug molecule binds to cause biological effects – It is also called lock and key system – Structure determination of receptor is important • Ligand-based drug design – Search a lead compound or active ligand – Structure of ligand guide the drug design process
  18. 18. 3D Visualization • X-ray crystallography and NMR Spectroscopy can reveal 3D structure of protein and bound compounds • Visualization of these “complexes” of proteins and potential drugs can help scientists understand the mechanism of action of the drug and to improve the design of a drug • Visualization uses computational “ball and stick” model of atoms and bonds, as well as surfaces • Stereoscopic visualization available
  19. 19. Binding Site Identification • Before beginning molecular interaction calculations… • Where is the active site? ?
  20. 20. Molecular Interaction concept
  21. 21. Overview Continued – A simple example Protein Small molecule drug Protein Function Switch ON or OF
  22. 22. The Crystal Structure Determination of a Protein (PDB:1DPY)
  23. 23. The Crystal Structure Determination of a Protein (PDB:1DPY)
  24. 24. Active Site region (PDB:1DPY) ASP 49 & HIS48
  25. 25. High-Throughput Screening • Drug companies now have millions of samples of chemical compounds. • High-throughput screening can test 100,000 compounds a day for activity against a protein target. • Maybe tens of thousands of these compounds will show some activity for the protein. • The chemist needs to intelligently select the 2 - 3 classes of compounds that show the most promise for being drugs to follow-up. ?
  26. 26. High-Throughput Screening
  28. 28. Molecular Modeling 3D Visualization of interactions between compounds and proteins
  29. 29. Template(s) selection Sequence Alignment Structure Modeling StructureEvaluation Final Structural Models Target sequence Sequence retriew from NCBI Database Known Structures (templates) STEPS PHYRES online template search tool http://www.sbg.bio.ic.ac.uk/phyre Sequence Similarity / Fold recognition. Structure quality (resolution, experimental method)Experimental conditions Template model & satisfaction of Spatial Restraints: MODELLER Structure properties & function study Pharmacophore Identification
  30. 30. In Silico ADME Models • Computational methods can predict compound properties important to ADME, e.g. – LogP, a liphophilicity measure – Solubility – Permeability – Cytochrome p450 metabolism • Means estimates can be made for millions of compounds, helping reduce “attrition” – the failure rate of compounds in late stage
  31. 31. Major Molecular Interaction or Docking Software's Accelrys discovery studio (commercial) Schrödinger Suit (one year student licence) AutoDock Tool (Academic version free) Other: • Gold • ICM-PRO
  32. 32. Directory of computer-aided Drug Design tools
  33. 33. Thank You