Download - Computers overview
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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