Drug Design

1. Lead Identification
&
Lead Optimization
By
Dr SK ARIFA BEGUM
Avanthi Institute of Pharmaceutical Sciences

2. Drug Discovery
The drug discovery process generally follows the following path that
includes a hit to lead stage:
•Target Validation (TV) → Assay Development → High-Throughput
Screening (HTS) → Hit to Lead (H2L) → Lead Optimization (LO) → Pre-
Clinical Drug Development → Clinical Drug Development
•Lead Identification

6. Drug Design
Lead Optimization
By
Dr SK ARIFA BEGUM
Avanthi Institute of Pharmaceutical Sciences

7. Lead optimization
Lead identification/optimization is the one of the most important steps in drug
development.
The chemical structure of the lead compound is used as a starting point for chemical
modifications.
These lead compounds undergo more extensive optimization in a subsequent step of
drug discovery called lead optimization(LO).
Purpose
In order to improve potency, selectivity, or pharmacokinetic parameters.
Once a molecule is identified, the next step is to check its ADMET (Adsorption,
Distribution, Metabolism, Excretion and Toxicity) properties.
If the molecule has no toxicity and no mutagenicity either, it has potential for use as
lead molecule.
Further optimization gives better quality of lead molecules. These may subsequently be
developed as drug(s)
Objective
Lead molecule should be modified to get safe and effective drug molecule which could
be achieved i.e by performing the in silico studies using some software tools.
i.e the designed drug molecule should have druglikeness and should be nontoxic and
also should not bind to the offtargets. This can be ensured using various softwares and
in silico tools.

13. S.No Tool Description
1 PreADMET a web-based application for
predicting ADME data and building
drug-like library using in silico
method
2 Molinspiraton Calculation of Molecular Properties
and Drug-likeness
3 EDragon application for the calculation of
molecular descriptors
4 MODEL - Molecular Descriptor Lab Computing structural and
physichemical properties of
molecules from their 3D structures.
5 Swiss ADME Calculation of oral/intestinal
absorption and BBB permeation
6 Swiss Target Prediction of the possible targets for
the designed molecules
7 Swiss Dock Perform the molecular docking
studies and calculate the binding
affinities (ΔG)

14. Types of Drug Design
By
Dr SK ARIFA BEGUM
Avanthi Institute of Pharmaceutical Sciences

15. Drug Discovery
The drug discovery process generally follows the following path that includes a hit
to lead stage:
•Target Validation (TV)
•→ Assay Development
•→High-Throughput Screening (HTS)
• →Hit to Lead (H2L)
•→Lead Optimization (LO)
•→ Pre-Clinical Drug Development
•→ Clinical Drug Development

16. TYPES OF DRUG DESIGN
The drug is most commonly an organic small molecule that activates or inhibits
the function of a biomolecule such as a protein, which in turn results in a
therapeutic benefit to the patient.
In the most basic sense, drug design involves the design of small molecules
that are complementary in shape and charge to the biomolecular target with
which they interact and therefore will bind to it.
Typically a drug target is a key molecule involved in a particular metabolic or
signaling pathway that is specific to a disease condition or pathology or to the
infectivity or survival of a microbial pathogen.
Ligand-based drug design Also called indirect drug design which relies on
knowledge of other molecules that bind to the biological target of interest.
These other molecules may be used to derive a pharmacophore* model that
defines the minimum necessary structural characteristics a molecule must
possess in order to bind to the target.

18. Structure-based drug design
Also called direct drug design which relies on knowledge of the three dimensional
structure of the biological target obtained through methods such as x-ray
crystallography or NMR spectroscopy.
If an experimental structure of a target is not available, it may be possible to create a
homology model of the target based on the experimental structure of a related
protein.
Current methods for structurebased drug design can be divided roughly into two
categories.
(1)“finding” ligands for a given receptor using database search a large number of
potential ligand molecules are screened to find those fitting the binding pocket of the
receptor. The key advantage of database searching is that it saves synthetic effort to
obtain new lead compounds.
(2) “building” ligands Ligand molecules are built up within the constraints of the
binding pocket by assembling small pieces in a stepwise manner. These pieces can be
either individual atoms or molecular fragments. The key advantage of such a method
is that novel structures, not contained in any database, can be suggested.

20. The process of structure-based drug design is an iterative one (see Figure) and often
proceeds through multiple cycles before an optimized lead goes into phase I clinical
trials.
The first cycle includes the cloning, purification and structure determination of the
target protein or nucleic acid by X-ray crystallography, NMR, or homology modeling.
Using computer algorithms, compounds or fragments are positioned into a selected
region of the structure.
 These compounds are scored and ranked based on their steric and electrostatic
interactions with the target site, and the best compounds are tested with biochemical
assays.
 In the second cycle structure determination of the target in complex with a promising
lead from the first cycle, one with at least micromolar inhibition in vitro, reveals sites on
the compound that can be optimized to increase potency.
Additontional cycles include synthesis of the optimized lead, structure determination of
the new target:lead complex, and further optimization of the lead compound.
After several cycles of the drug design process, the optimized compounds usually

21. Overall steps involved
Link the fragments- Grow the fragments-Score the functions
Active site identification of the target biomolecule
Active site identification is the first step It analyzes the protein to find the binding
pocket, derives key interaction sites within the binding pocket, and then prepares the
necessary data for Ligand fragment link.
The basic inputs for this step are the 3D structure of the protein and a pre-docked
ligand in PDB format, as well as their atomic properties. Both ligand and protein
atoms need to be classified and their atomic properties should be defined, basically,
into four atomic types: • hydrophobic atom:
All carbons in hydrocarbon chains or in aromatic groups. • H-bond donor: Oxygen
and nitrogen atoms bonded to hydrogen atom(s). • H-bond acceptor: Oxygen and
sp2 or sp hybridized nitrogen atoms with lone electron pair(s).
• Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond
acceptor, sulfur, phosphorus, halogen, metal, and carbon atoms bonded to hetero-
atom(s).

22. Application of Structure based drug design
•approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved in
1995.
•Imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein
•Design of antipsychotics
•Cimetidine , the prototypical H2-RECEPTOR ANTAGONIST FROM WHICH THE LATER
MEMBERS OF THE CLASS WERE DEVELOPED
•Selective COX-2 inhibitors- NSAIDS
•Enfuvirtide, apeptide HIV entry inhibitor
•Nonbenzodiazepines like zolpidem, and zopiclone
•Selective serotonin reuptake inhibitors, a class of anti depressants
•Zanamivir, an antiviral drug
•Isentress,HIV Integrase inhibitors

23. PHARMACOPHORE IDENTIFICATION
Computational chemists working in the area of structure-based drug design consider
both chemical and geometric properties of the interacting molecules when developing
new pharmaceutical drugs .
The underlying assumption is that drug activity, or pharmacophoric activity, is obtained
through the molecular recognition and binding of one molecule (ligand) to a pocket of
another, usually larger, molecule (receptor).
This assumption is supported by experimental results showing molecules with geometric
and chemical complementarity in their binding conformations . When the three-
dimensional structure of the receptor is known, docking methodsn exploit both the
geometric and the chemical information available.
However, the geometric structures of relatively few molecules have been obtained via
X-ray crystallography or NMR techniques.
In an effort to develop pharmaceutical drugs for receptors whose structure is unknown,
chemists start with a collection of ligands that have been experimentally discovered to
interact with the considered receptor.
By examining the chemical properties and the possible shapes of these ligands, they try

24. The features of the pharmacophore interact with features of the receptor, while the
rest of the ligand acts as a scaffold. Once a pharmacophore has been isolated, it can
be used to further improve the activity of a pharmaceutical drug.
A pharmacophore is an ensemble of steric and electronic features that is necessary to
ensure the optimal supramolecular interactions with a specific biological target and to
trigger or block ita biological response.
The pharmacophore model can be used to identify novel ligands that will bind to the
same receptor.Historically, pharmacophores were established by Lemon Kier, developed
by Paul Ehrlich.
Once the pharmacophore is identified structural modifications can be done to improve
the pharmacokinetic properties of the drug. For example the presence of the phenyl
ring , asymmetric carbon, ethylene bridge and teritiary nitrogen are found to be
minimum structural requirement for a narcotic analgesic to become active.Similarly
presence of two anionic sites and one cationic site must be present in cholinergic
agent.
Morphine, the prototype narcotic agent has a pentacyclic structure. The complexityof
the structure leads to appearance of several side effects.

26. Typical pharmacophore features include
Hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors , cations and
anions.
These pharmacophore points may be located on the ligand itself
Or
May be projected points presumed to be located in the receptor.
These features need to match different chemical groups with similar properties in order
to identify novel ligands.
Ligand – receptor interactions are typically “polar positive”, “polar negative” or
“hydrophobic”.