Computer Use in Medicinal

Chemistry
Overview of Computer-
1. Finding/storing information
Aided Drug Design 1. Literature searching (Medline, SciFinder…)
2. Structure searching (Protein Databank,
SciFinder)
3. Cataloging structure-activity data
2. Modeling existing lead compounds
3. Developing new lead compounds

NO
Is Target Structure Known?

YES
Modeling Existing Lead
PHARMACOPHORE-BASED APPROACHES STRUCTURE-BASED APPROACHES
Compounds
Generate Working Models of Ligands Generate Working Model of Target l QSAR
l Development of a mathematical model that describes in a predictive
manner the relationship between structure (represented by
numerical descriptors) and activity
Characterize Active Site
QSAR 3D QSAR Qualitative SAR (grid-based electrostatic potential...)
l Pharmacophore Model Development
l Finding a set of functional groups with the same geometric
arrangement in a series of compounds with a common biological
GENERATE NEW LEAD STRUCTURES activity
Propose New Lead or Optimize Existing Lead l 3D QSAR
(De Novo Design, Database Search, Combinatorial Chemistry...)
l Development of a quantitative model relating structure to biological
EVALUATE NEW STRUCTURES
activity in which the structural descriptors are values for various
properties computed at grid points in three-dimensional space
l Docking
Is Protein Structure Known?
l Development of a model complex of a biological target and a ligand
NO YES
l Free Energy Perturbation
QSAR or 3D QSAR model, Docking, FEP, Hydration Free Energy, l A computational method to determine the differences in free energy
Hydration Free Energy... Regression Methods... involved in transferring different ligands from the aqueous solution to
a binding site in a biological target
Synthesize/Test Best Candidates

Group Discussion Group Discussion Points

l Questions
l Identify some important questions or l QSAR – Can QSAR be used with other identification
limitations of technique based on concepts processes? (spectroscopic)
l Pharmacophore Modeling – Need to determine
from organic chemistry pharmacophore grps in each molecule with similar
characteristics
Typical chapter titles in organic chemistry textbooks: l Docking – need structures (stereochemistry often not
known for initial lead compounds)
Structure and bonding; Bonding and molecular properties; Alkanes and
cycloalkanes; Stereochemistry; Overview of organic reactions; Alkenes; Alkynes; l Limitations
Alkyl halides; Nucleophilic substitutions and eliminations; Structure determination l QSAR – No visual aspect (how to improve activity not
(spectroscopy); Conjugated dienes; Benzene and aromaticity; Electrophilic
intuitive)
aromatic substitution; Alcohols and thiols; Ethers, epoxides and sulfides;
Nucleophilic addition to carbonyls; Carboxylic acids; Carboxylic acid derivatives; l Pharmacophore Modeling – Limited to functional groups of
Carbonyl alpha-substitution reactions; Carbonyl condensation reactions; similar charge and size
Aliphatic amines; Arylamines and phenols; Carbohydrates; Amino acids, l Docking – Does not anticipate potential chemical reactions
peptides and proteins; Lipids; Heterocycles and nucleic acids (covalent inhibition)

1
 Pharmacophore Modeling
QSAR Example Example
l Biological activity of indoleacetic acid-like The three molecules below all target protein kinase C

synthetic hormones Each molecule can adopt a conformation with common distances separating
the circled groups
l Log(1/C) = -k1(logP)2+k2(logP)+K3σ+k4 O

l C: Concentration having a standard response in a Endogenous R O H OH

Activator R O OH N CH3
standard time R Antitumor
O O Compound
l P: Octanol/water partition coefficient (S)-DAG
O OH O OCH3
l Log P reflects pharmacokinetic influence on activity –
O O
does the compound get where it needs to go?
σ reflects pharmacodynamic influence on activity – R O O R HO
l O
does the electronic nature of the compound induce H3C CH3 O OH O
Tumor AD 198
activity? Promoter
HO
O

H3 OH
C Phorbol Ester
O

3D QSAR Example
J Mol. Graph. Model. 21 (2003) 263-272
Docking Example

Blue: Negative charge disfavored Docking was used to identify the

binding site of a phospholipid in a G
Red: Negative charge favored
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
Green: Sterically disfavored binding
Yellow: Sterically allowed

Analysis Exercise Free Energy Perturbation

l Visually examine the 1HNI structure of HIV
reverse transcriptase ∆GBind1
Ligand 1 Solvated Ligand 1 Bound

l Focus on the inhibitor and the surrounding ∆GSolv ∆GInter

∆GBind2
residues Ligand 2 Solvated Ligand 2 Bound
l What type of intermolecular interactions can
you identify visually? Most useful quantity to compare drug candidates:
∆GBind1 – ∆GBind2
l Which ones do you think are most important? 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 + ∆GBind2
Rearrangement demonstrates the previous differences are equivalent

2
 Is Target Structure Known?

NO YES

Developing New Leads PHARMACOPHORE-BASED APPROACHES STRUCTURE-BASED APPROACHES

Generate Working Models of Ligands Generate Working Model of Target

l De novo Design
l Techniques that build a potential ligand into the
Characterize Active Site
environment of a biological target of known structure QSAR 3D QSAR Qualitative SAR (grid-based electrostatic potential...)

l Database searching GENERATE NEW LEAD STRUCTURES

l Use of pharmacophore models to query a database for Propose New Lead or Optimize Existing Lead
new structures that also contain the requisite 3D (De Novo Design, Database Search, Combinatorial Chemistry...)

arrangement of functional groups EVALUATE NEW STRUCTURES

l Combinatorial library design

Is Protein Structure Known?
l Use of computers to determine a library of compounds NO YES
enriched in potentially active compounds that can be
QSAR or 3D QSAR model, Docking, FEP, Hydration Free Energy,
synthesized combinatorially and rapidly screened Hydration Free Energy... Regression Methods...

Synthesize/Test Best Candidates

Reading Assignment
l The Organic Chemistry of Drug Design and
Drug Action
l Chapter 2:
l Section 2.2 A, C, D, G1, H, I
l Textbook of Drug Design and Discovery
l Sections 4.1-4.3
l Sections 5.1-5.2