1

Overview of Computer-Aided Drug Design

Computer Use in Medicinal Chemistry

1. Finding/storing information1. Literature searching (Medline, SciFinder…)2. Structure searching (Protein Databank,

SciFinder)3. Cataloging structure-activity data

2. Modeling existing lead compounds3. Developing new lead compounds

Is Target Structure Known?

NO YES

Generate Working Model of Target

QSARCharacterize Active Site

(grid-based electrostatic potential...)

Propose New Lead or Optimize Existing Lead(De Novo Design, Database Search, Combinatorial Chemistry...)

PHARMACOPHORE-BASED APPROACHES STRUCTURE-BASED APPROACHES

3D QSAR Qualitative SAR

Generate Working Models of Ligands

Is Protein Structure Known?

EVALUATE NEW STRUCTURES

YESNO

Docking, FEP, Hydration Free Energy, Regression Methods...

QSAR or 3D QSAR model, Hydration Free Energy...

Synthesize/Test Best Candidates

GENERATE NEW LEAD STRUCTURES

Modeling Existing Lead Compoundsl QSAR

l Development of a mathematical model that describes in a predictive manner the relationship between structure (represented by numerical descriptors) and activity

l Pharmacophore Model Developmentl Finding a set of functional groups with the same geometric

arrangement in a series of compounds with a common biological activity

l 3D QSARl Development of a quantitative model relating structure to biological

activity in which the structural descriptors are values for various properties computed at grid points in three-dimensional space

l Dockingl Development of a model complex of a biological target and a ligand

l Free Energy Perturbationl A computational method to determine the differences in free energy

involved in transferring different ligands from the aqueous solution to a binding site in a biological target

Group Discussion

l Identify some important questions or limitations of technique based on concepts from organic chemistry

Typical chapter titles in organic chemistry textbooks:

Structure and bonding; Bonding and molecular properties; Alkanes and cycloalkanes; Stereochemistry; Overview of organic reactions; Alkenes; Alkynes; Alkyl halides; Nucleophilic substitutions and eliminations; Structure determination (spectroscopy); Conjugated dienes; Benzene and aromaticity; Electrophilicaromatic substitution; Alcohols and thiols; Ethers, epoxides and sulfides; Nucleophilic addition to carbonyls; Carboxylic acids; Carboxylic acid derivatives; Carbonyl alpha-substitution reactions; Carbonyl condensation reactions; Aliphatic amines; Arylamines and phenols; Carbohydrates; Amino acids, peptides and proteins; Lipids; Heterocycles and nucleic acids

Group Discussion Pointsl Questionsl QSAR – Can QSAR be used with other identification

processes? (spectroscopic)l Pharmacophore Modeling – Need to determine

pharmacophore grps in each molecule with similar characteristics

l Docking – need structures (stereochemistry often not known for initial lead compounds)

l Limitationsl QSAR – No visual aspect (how to improve activity not

intuitive)l Pharmacophore Modeling – Limited to functional groups of

similar charge and sizel Docking – Does not anticipate potential chemical reactions

(covalent inhibition)

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QSAR Example

l Biological activity of indoleacetic acid-like synthetic hormones

l Log(1/C) = -k1(logP)2+k2(logP)+K3σ+k4l C: Concentration having a standard response in a

standard timel P: Octanol/water partition coefficientl Log P reflects pharmacokinetic influence on activity –

does the compound get where it needs to go?l σ reflects pharmacodynamic influence on activity –

does the electronic nature of the compound induce activity?

Pharmacophore Modeling Example

The three molecules below all target protein kinase C

Each molecule can adopt a conformation with common distances separating the circled groups

R O OH

O

OR

O

H3C

O

OH

H3CHO

CH3

OOR

O

R

OOCH3O

OOH

OHO

HO

O

CH3

OHHN

R

OO

O

EndogenousActivator

TumorPromoter

AntitumorCompound(S)-DAG

Phorbol Ester

AD 198

3D QSAR Example

Green: Sterically disfavored

Yellow: Sterically allowed

Blue: Negative charge disfavored

Red: Negative charge favored

J Mol. Graph. Model. 21 (2003) 263-272 Docking Example

Docking was used to identify the binding site of a phospholipid in a G protein-coupled receptor

Three key ion pairing interactions between the receptor and the phospholipid are highlighted in panel C

Experimental mutation of ARG120, GLU121, and ARG292 to ALA resulted in complete loss of phospholipid binding

Analysis Exercise

l Visually examine the 1HNI structure of HIV reverse transcriptase

l Focus on the inhibitor and the surrounding residues

l What type of intermolecular interactions can you identify visually?

l Which ones do you think are most important?

Free Energy Perturbation

Ligand 1 Solvated Ligand 1 Bound

Ligand 2 Solvated Ligand 2 Bound

∆GBind1

∆GBind2

∆GSolv∆GInter

Most useful quantity to compare drug candidates:∆GBind1 – ∆GBind2

Most computationally feasible quantity:∆GSolv – ∆GInter

Since free energy is a state function, any path with the same beginning and end points has the same value, therefore ∆GBind1+ ∆GInter = ∆GSolv + ∆GBind2Rearrangement demonstrates the previous differences are equivalent

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Developing New Leads

l De novo Designl Techniques that build a potential ligand into the

environment of a biological target of known structure

l Database searchingl Use of pharmacophore models to query a database for

new structures that also contain the requisite 3D arrangement of functional groups

l Combinatorial library designl Use of computers to determine a library of compounds

enriched in potentially active compounds that can be synthesized combinatorially and rapidly screened

Is Target Structure Known?

NO YES

Generate Working Model of Target

QSARCharacterize Active Site

(grid-based electrostatic potential...)

Propose New Lead or Optimize Existing Lead(De Novo Design, Database Search, Combinatorial Chemistry...)

PHARMACOPHORE-BASED APPROACHES STRUCTURE-BASED APPROACHES

3D QSAR Qualitative SAR

Generate Working Models of Ligands

Is Protein Structure Known?

EVALUATE NEW STRUCTURES

YESNO

Docking, FEP, Hydration Free Energy, Regression Methods...

QSAR or 3D QSAR model, Hydration Free Energy...

Synthesize/Test Best Candidates

GENERATE NEW LEAD STRUCTURES

Reading Assignment

l The Organic Chemistry of Drug Design and Drug Actionl Chapter 2:l Section 2.2 A, C, D, G1, H, I

l Textbook of Drug Design and Discoveryl Sections 4.1-4.3l Sections 5.1-5.2