Pract Drug

7/28/2019 Pract Drug

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Molecular Conceptor - Table of Contents

Practical Drug Discovery: Case StudiesLast updated on September 2012

A - DRUG DISCOVERY

1. Case Studies in SAR Analyses

2. Success Stories in Drug Discovery

B - ANALOG DESIGN AND MOLECULAR MIMICRY

1. Case Studies in Advanced Analog Design

2. Case Studies in 3D Mimic Design

3. Case Studies in Peptidomimetics

C - SYNTHESIS AND LIBRARY DESIGN

1. Case Studies in Library Design

D - ADME PROPERTIES AND PREDICTIONS

1. Case Studies in ADME/Tox Predictions

E - STRUCTURE-BASED DESIGN

1. Case Studies in Structure-Based Design

2. Case Studies of Docking in Drug Discovery

F - CHEMINFORMATICS

1. Case Studies in 3D Database Searching

G - LIGAND-BASED DESIGN

1. Case Studies in Ligand-Based Design

H - QSAR AND CHEMOMETRICS

1. Case Studies in QSAR and 3D-QSAR

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A. DRUG DISCOVERY

A1. CASE STUDIES IN SAR ANALYSES

A1.1 Case Study-1 : Banyu Example

A1.1.1 The Banyu Story with the Urea Structure

A1.1.2 Importance of the Entire Urea Moiety

A1.1.3 Bioactive Conformation?

A1.1.4 Design of Compounds with a Cis Conformation

A1.1.5 Good Exploitation of the SAR Analyses

A1.2 Case Study-2 : Dioxobenzothiazole Example

A1.2.1 The Dioxobenzothiazole Scaffold

A1.2.2 Optimization of the Dioxobenzothiazole Lead

A1.2.3 SAR Analyses

A1.2.4 Docking of the Dioxobenzothiazole Molecule

A1.2.5 Being Trapped with a Bad Scaffold

A1.3 Case Study-3 : EGF-R Kinase Inhibitors

A1.3.1 Therapeutic Utility of EGF-R Kinase Inhibitors

A1.3.2 Amino-4 Quinazoline Inhibitors: Iressa and Tarceva

A1.3.3 Analysis of Tarceva Binding to the EGF-R Kinase (1/4)




A1.3.7 SAR of the Quinazoline Scaffold

A1.3.8 SAR of Fused Rings in the Quinazoline Scaffold

A1.3.9 Analysis of a Surprising Observation

A1.3.10 Analysis of Atomic Charges in the Different Analogs

A1.3.11 Optimal Binding of Inhibitor 17

A1.4 Case Study-4 : Nifedipine Example

A1.4.1 Two Inactive Analogs of Nifedipine

A1.4.2 Analysis of the 4' Substituted Analogs of Nifedipine

A1.4.3 Analysis of the 4 Substituted Analogs of Nifedipine

A1.4.4 Molecular Geometry of Phenyl-4 Dihydropyridine

A1.4.5 Preferred Conformation of Nifedipine

A1.4.6 Preferred Conformation of Methyl-4 Nifedipine

A1.4.7 Bioactive Conformation of Nifedipine-Like Antagonists A1.4.8 SAR Analyses Require Great Attention

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A1.7 Case Study-7 : Anilino-Quinazoline Example

A1.7.1 Potent Inhibitor of the EGF-R Protein Kinase

A1.7.2 SAR: Substitution of Anilino N4

A1.7.3 N-Methyl Analog A1.7.4 SAR Observations in a 4-Anilino-Quinazolines Series

A1.7.5 Conformation of 4-Anilino-Quinazoline Molecules

A1.7.6 Geometry of 4-Anilino-Quinazoline Structures

A1.7.7 Experimental Conformations of Anilino-Quinazolines

A1.7.8 SAR: Substitution of N4 is Detrimental to Potency

A1.7.9 Torsion Angle N3-C4-N4-C1' is Important for Potency

A1.7.10 Energy of Bioactive Conformers

A1.7.11 Browser of Selected Anilino-Quinazoline Analogs

A1.7.12 Docking of 4-Anilino-Quinazoline Lead

A1.7.13 Summary of Structural Analyses

A1.8 ADDITIONAL CASE STUDIES

A1.8.1 Additional Case Studies

A2. SUCCESS STORIES IN DRUG DISCOVERY

A2.1 Success Story-1 : Captopril

A2.1.1 Captopril

A2.1.2 Captopril Target - ACE

A2.1.3 Starting Point: Venom Causes Drop in Blood Pressure

A2.1.4 Snake Venom Acts on the ACE Cascade

A2.1.5 The Captopril Story

A2.1.6 Developing an Assay for ACE

A2.1.7 Isolating and Purifying the Venom Peptides

A2.1.8 Encouraging Clinical Trial Results

A2.1.9 Project Virtually Abandoned at Squibb

A2.1.10 Back to the Project

A2.1.11 Applying the Concepts to ACE

A2.1.12 The Basis of ACE and CPA Similarity

A2.1.13 X-ray Structure of CPA

A2.1.14 Modeling the Active Site of ACE (1/4)




A2.1.18 Design of a Novel ACE Inhibitor

A2.1.19 The Phe-Ala-Pro Pharmacophore

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A2.1.20 Finding a Lead Compound

A2.1.21 The Discovery of Captopril

A2.1.22 The Captopril Project Timeline

A2.1.23 What Made the Success of the Project Possible?

A2.1.24 Structure-Based Component A2.1.25 Ligand-Based Component

A2.1.26 Following the Discovery

A2.1.27 Recent Structure of Captopril-ACE Complex

A2.1.28 Other Drugs in This Class

A2.2 Success Story-2 : Aliskiren

A2.2.1 Aliskiren

A2.2.2 Aliskiren Target - Renin

A2.2.3 Starting Point

A2.2.4 The Aliskiren Story A2.2.5 The First Generation of Renin Inhibitors

A2.2.6 The Second Generation of Renin Inhibitors

A2.2.7 Peptidomimetic Approach was Unsuccessful

A2.2.8 The Need for a New Non-Peptidic Scaffold

A2.2.9 Novartis's New Rational Approach

A2.2.10 3D Model of the Enzyme

A2.2.11 Predicting the Bioactive Conformation of CGP38560

A2.2.12 The Design Strategy

A2.2.13 Finding a Feasible Scaffold

A2.2.14 Criteria for Good Candidate Molecules A2.2.15 The Parallel Design of Non-Peptide Renin Inhibitors

A2.2.16 The THQ Series

A2.2.17 Validation of the Design Strategy

A2.2.18 The Phenoxy Series

A2.2.19 Optimization of the Phenoxy Lead

A2.2.20 The Indole Series

A2.2.21 The Salicylamide Series

A2.2.22 A Docking Experiment

A2.2.23 Design of the Salicylamide Molecule

A2.2.24 Transferrable SAR's A2.2.25 Example of Transferrable SAR's

A2.2.26 Four Unrelated Lead Compounds

A2.2.27 Browser of the Novartis Renin Inhibitor Leads

A2.2.28 From Initial Lead to Aliskiren

A2.2.29 The Aliskiren Project Timeline

A2.2.30 What Made the Success of the Project Possible?

A2.2.31 The Incorporation of Modeling

A2.2.32 Modeling - The Key to Aliskiren's Success

A2.2.33 Historical Document

A2.2.34 Good Teamwork A2.2.35 Following the Discovery

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A2.2.36 X-rays of Complex with CGP38560

A2.2.37 X-ray Determination of Lead Inhibitors

A2.2.38 The Indole X-ray

A2.2.39 The S3sp sub-Pocket

A2.2.40 Other Work on Drugs in this Class

B. ANALOG DESIGN AND MOLECULAR MIMICRY

B1. CASE STUDIES IN ADVANCED ANALOG DESIGN

B1.1 Case Study-1 : Salicylanilides

B1.1.1 Salicylanilides

B1.1.2 Genistein Structure and Alignment with Quinazoline 1

B1.1.3 3D Design of a Salicylanilide Scaffold

B1.1.4 Possible Intramolecular H-Bonds in Salicylanilides

B1.1.5 Synthesis of the Molecules

B1.1.6 Biological Assays

B1.1.7 Validity of the Hypotheses

B1.1.8 Summary

B1.2 Case Study-2 : Pyrimidin-4-yl-ureas

B1.2.1 Pyrimidin-4-yl-ureas

B1.2.2 PD-166285 Reference and Novartis Design

B1.2.3 A Search in the Cambridge Structural Database

B1.2.4 Ab-Initio Calculations

B1.2.5 Synthesis of the Prototype Molecule

B1.2.6 Biological Assays for Pyrimidin-4-yl-urea

B1.2.7 Docking of Pyrimidin-4-yl-urea in c-Abl

B1.2.8 Correlation of the Activities with Size of Gate Keeper

B1.2.9 Alignment of Pyrimidin-4-yl urea and PD-166285

B1.2.10 P&G Discovered Independently the Same Molecule

B1.2.11 Optimization Towards Lck Kinase Inhibition

B1.2.12 Summary

B1.3 Case Study-3 : Anthranilamide Scaffold

B1.3.1 Anthranilamide Scaffold

B1.3.2 Structural Determinants of Anilinophtalazine Activity ?

B1.3.3 Conformational Analyses

B1.3.4 Bidentate Binding Mode Unlikely to Occur

B1.3.5 Role of the Nitrogen Phtalazine Atoms

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B1.3.6 Database Searching

B1.3.7 3D Electrostatic Potential

B1.3.8 Synthesis of the Exact Anthranilamide Mimetic

B1.3.9 Biological Tests

B1.3.10 3D Overlay of Mimic Structures B1.3.11 Determinants for Anilinophtalazine KDR/Flt-1 Activities

B1.3.12 Summary

B1.4 Case Study-4 : Phenoxyphenyltriazoles

B1.4.1 Phenoxyphenyltriazoles

B1.4.2 Requirements for Binding to the BZD Receptor

B1.4.3 Design of an Estazolam Mimic

B1.4.4 Conformational Analyses and Overlay with Diazepam

B1.4.5 Chemical Synthesis of the Mimics

B1.4.6 Confirmation of the Design Hypothesis B1.4.7 Summary

B1.5 Case Study-5 : Pro-Leu-Gly-NH2 Peptide

B1.5.1 Pro-Leu-Gly-NH2 Peptide

B1.5.2 The -Lactam Analog of Pro-Leu-Gly-NH2

B1.5.3 Design of Imidazolidinone and Diketopiperazine


B1.5.5 3D Alignment of Pro-Leu-Gly-NH2 and Mimics

B1.5.6 Summary

B1.6 Case Study-6 : Remoxipride Mimic

B1.6.1 Remoxipride Mimic

B1.6.2 Bioactive Conformation of Desmethylremoxipride

B1.6.3 Design of Rigid Analog

B1.6.4 Chemical Synthesis


B1.6.6 3D Alignments

B1.6.7 Summary

B1.7 Case Study-7 : Rimonabant Mimics

B1.7.1 Rimonabant Mimic

B1.7.2 Conformational Analysis of Rimonabant

B1.7.3 Design of Rigid Analog

B1.7.4 Chemical Synthesis


B1.7.6 3D Alignment of Rimonabant and Mimic

B1.7.7 Summary

B1.8 Case Study-8 : Salicylamide Mimics

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B1.8.1 Salicylamide Mimics

B1.8.2 SAR of Salicylamide 1

B1.8.3 Removing the Hydroxyl or the Carbonyl

B1.8.4 Analyzing if Ortho Electron Lone-Pair is Sufficient

B1.8.5 Potent Inhibition at Ki at Different pH B1.8.6 Pseudo-Ring of 1 Binds as a Whole Unit

B1.8.7 Design of Quinazoline Mimic

B1.8.8 3D Alignment of Salicylamide 1 and Quinazoiline 2

B1.8.9 Conclusion

B1.8.10 Summary

B1.9 Case Study-9 : Bradykinin Antagonists

B1.9.1 Bradykinin Antagonists

B1.9.2 The Problem

B1.9.3 The Stepwise Discovery of Cyclopropylamide B1.9.4 Retaining the two N-H groups

B1.9.5 Mimicking the Nitrogen Pyridine Atom by a Carbonyl

B1.9.6 Conformational Considerations

B1.9.7 First Molecules Synthesized

B1.9.8 Restoring Lipophilic Interactions

B1.9.9 Reducing Ring Size

B1.9.10 The Best Replacement

B1.9.11 Additional Factors in Cyclopropyl Replacement

B1.9.12 Torsion Angle N-C-C-N

B1.9.13 Smaller Rings have Increasing Character B1.9.14 Ring Strain and Geometry of Cyclopropyl

B1.9.15 Bulkiness of the Hydrophobic Ring

B1.9.16 3D Alignment of 1 and the Cyclopropyl Surrogate

B1.9.17 Summary

B1.9.18 Factor Xa Inhibitors

B1.9.19 Factor Xa Inhibitors with 2,3-Diaminopyridine Core

B1.9.20 Replacement May be of General Utility

B1.9.21 Surrogates Generated by Computer

B1.10 ADDITIONAL CASE STUDIES

B1.10.1 Additional Case Studies

B2. CASE STUDIES IN 3D MIMIC DESIGN

B2.1 Case Study-1 : Cimetidine Mimicry

B2.1.1 Two Very Different H2-Antagonists

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B2.1.2 Cimetidine has a Folded Conformation

B2.1.3 3D Mimicry between Cimetidine and Triazole

B2.2 Case Study-2 : Substance P Antagonists

B2.2.1 Substance P : a Ligand of CNS Receptors

B2.2.2 Conformation of Substance P

B2.2.3 Template for Mimicking the Phe-Phe Moiety

B2.2.4 The Successful Discovery of SP Antagonists

B2.2.5 A Phe-Phe Mimic of Substance P

B2.2.6 Mimicry of CGP-47899 and Substance P

B2.3 Case Study-3 : Hypolipemic Agents

B2.3.1 Reference Set of Hypolipemic Agents

B2.3.2 Design of a New Hypolipemic Agent

B2.3.3 RU 25961 is a 3D Mimic of Treloxinate

B2.3.4 Browser of Hypolipemic Agents

B2.3.5 Methyl Treloxinate

B2.3.6 Biological Activities of Cis and Trans Isomers

B2.3.7 Browser of Hypolipemic Agents

B2.4 Case Study-4 : Polymerase-1 Inhibitors

B2.4.1 Therapeutic utility of PARP-1 Inhibitors

B2.4.2 3-Amino Benzamide PARP-1 Inhibitor

B2.4.3 Design with Carboxamide Geometry Locked B2.4.4 3D Mimicry between Structure C and NU-1085

B2.4.5 Synthesis of the Designed Tricyclic Compounds

B2.4.6 Validation of the Concept by X-Ray Crystallography

B2.4.7 Browser of PARP-1 Inhibitors

B2.5 Case Study-5 : Angiotensin-II Antagonists

B2.5.1 Antagonists of Angiotensin-II Receptors

B2.5.2 Losartan as a Mimic of Angiotensin-II (1/5)





B2.5.7 Browser of Angiotensin-II Antagonists

B2.6 Case Study-6 : Cholecystokinin Receptor Ligands

B2.6.1 Design of Cholecystokinin Receptor Ligands

B2.6.2 Pharmacophore Analysis: CCK-A Antagonists (1/3)



B2.6.5 Design of a New Lorglumide Analog

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B2.7 Case Study-7 : Farnesyltransferase Inhibitors

B2.7.1 Farnesyltransferase, a Target in Oncology

B2.7.2 X-ray Structure of FTase with a Tetrapeptide

B2.7.3 Binding Interactions of CAAX Substrate for FTase B2.7.4 4-Aminobenzoic Spacer to Replace Val-Ile Dipeptide

B2.7.5 Superposition with X-Ray Structure of Initial Tripeptide

B2.7.6 The Simple Aromatic Central Ring is not Sufficient

B2.7.7 Analogs with Significantly Enhanced Potency

B2.7.8 3D Mimicry of FTI-276 and Reference Tetrapeptide

B2.7.9 Docking of FTI-276 and Reference Tetrapeptide

B2.7.10 Terphenyl to Replace the Central Val-Ile Dipeptide

B2.7.11 Alignment of FTI-289 with Cys-Val-Ile-Met

B2.7.12 Potent and Selective Farnesyltransferase Inhibitor

B2.7.13 X-ray of Abbott-21 bound to Farnesyltransferase

B2.7.14 Browser of Farnesyltransferase Inhibitors

B2.8 Case Study-8 : Antagonists of the Mdm2-p53 Interaction

B2.8.1 Antagonists of the Mdm2-p53 Interaction

B2.8.2 Mdm2 Bound to p53 Transactivation Domain (1/4)




B2.8.6 Systematic SAR Studies

B2.8.7 Contribution of the Amino-Acids to the Binding B2.8.8 3D Structure of the Pharmacophore

B2.8.9 The Novartis 5 nM Peptide-Like Antagonist

B2.8.10 Peptide 2 Designed to Stabilize Helical Conformations

B2.8.11 Peptide 3 Designed for a Salt Bridge with a Tyrosine

B2.8.12 Filling Empty Space Identified by Modeling

B2.8.13 Problems with the Peptide-Based Antagonists

B2.8.14 The Bicyclo [2.2.1]-Heptane Scaffold

B2.8.15 Designed Scaffold Aligned with the Pharmacophore



B3. CASE STUDIES IN PEPTIDOMIMETICS

B3.1 Case Study-1 : Somatostatin Mimicry

B3.1.1 Somatostatin Structure

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B3.1.2 Somatostatin Receptors

B3.1.3 Subtypes of Somatostatin Receptors

B3.1.4 The Drug Discovery Strategy

B3.1.5 The Somatostatin Pharmacophore

B3.1.6 Successful Reduction of the Somatostatin B3.1.7 Mimics of L-363,377 with Database Searching

B3.1.8 Results of the Database Searching

B3.1.9 A Good Mimic of the Reference Cyclic Peptide

B3.1.10 Development of a Combinatorial Chemistry Approach

B3.1.11 Combinatorial Chemistry Results

B3.1.12 An Integrated Approach to Drug Discovery

B3.2 Case Study-2 : -Opioid Receptor Agonists

B3.2.1 Therapeutic utility of-Opioid Receptor Agonists

B3.2.2 Typical Peptide -Opioid Receptor Agonists B3.2.3 Typical Non-Peptide -Opioid Receptor Agonists

B3.2.4 Pharmacophore for -Opioid Receptor Agonists

B3.2.5 SAR, NMR and Modeling of the DPDPE series (1/3)



B3.2.8 Bioactive Conformation of DPDPE (1/4)




B3.2.12 Scaffold Design of Non-Peptide Antagonists B3.2.13 Refinement of the Scaffold and Substituents

B3.2.14 Amino Group not Included

B3.2.15 Reducing the Number of Chiral Centers

B3.2.16 Substituent with Variable Hydrophobicity

B3.2.17 The First Series Synthesized

B3.2.18 The (-) SL-3111 Enantiomer

B3.3 Case Study-3 : MC4R Melanocortin Receptor Agonists

B3.3.1 Melanocortin Receptors

B3.3.2 Minimal Peptide Sequence for Activating the Receptor

B3.3.3 Strategy for the Design of New Agonists

B3.3.4 Cyclic Peptide 1

B3.3.5 Molecular Geometry of the Cyclic Peptide

B3.3.6 Design of Molecules with a Cyclohexane Core

B3.3.7 Acyl Groups to Keep the Compound Neutral

B3.3.8 Cis and Trans Cyclohexane Isomers

B3.3.9 Cis Isomer

B3.3.10 Trans Isomer

B3.3.11 Geometry of Cis Isomer with Tryptamine Equatorial

B3.3.12 Geometry of Cis Isomer with Tryptamine Axial

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B3.3.13 Geometry of Trans Isomer: Substituents Equatorial

B3.3.14 Cis Isomer Equatorial Aligned with Peptidic Agonist

B3.3.15 Cis Isomer Axial Aligned with Peptidic Agonist

B3.3.16 Trans Isomer Aligned with Peptidic Agonist

B3.3.17 Discovery of a Nanomolar Non-Peptidic Agonist B3.3.18 A Good Starting Point for Further Developments

B3.4 Case Study-4 : Renin Inhibitors

B3.4.1 The Renin-Angiotensin System Cascade

B3.4.2 The First Generation of Renin Inhibitors

B3.4.3 Example of Inhibitor

B3.4.4 The Second Generation of Renin Inhibitors

B3.4.5 Low Oral Absorption of CGP-38560

B3.4.6 Bioactive Conformation of CGP-38560

B3.4.7 Analysis of the Predicted Bioactive Conformation B3.4.8 Strategy for the Design of Non-Peptidic Inhibitors

B3.4.9 Successful Design of a Non-Peptidic Inhibitor

B3.4.10 Optimization of the Tetrahydroquinoline Inhibitor

B3.4.11 A Third Generation of Renin Inhibitors

B3.4.12 Alignment of the Non-Peptide Inhibitors in 3D

B3.5 Case Study-5 : Inhibitors of HLE

B3.5.1 Inhibition of Human Leukocyte Elastase

B3.5.2 Problem of Peptide-Based ICI-200,880

B3.5.3 TFMK as a Reference

B3.5.4 Analysis of the Binding of TFMK (1/4)




B3.5.8 Summary of the Analyses

B3.5.9 Design of a New Pyridone Framework

B3.5.10 3D Superimposition with TFMK

B3.5.11 Synthesis of Pyridone Molecule

B3.5.12 3D Geometry Maintained after Removal of Proline

B3.5.13 Analysis of the Pyridone Bound to PPE

B3.5.14 Optimization of the Pyridone Series

B3.5.15 Browser of HLE Inhibitors



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C. SYNTHESIS AND LIBRARY DESIGN

C1. CASE STUDIES IN LIBRARY DESIGN

C1.1 Case Study-1 : CDK2 Inhibitors

C1.1.1 Purine Scaffold as a Source of Bioactive Molecules

C1.1.2 CDK2 Biological Target and Known Inhibitors

C1.1.3 Diverse 2,6,9-trisubstituted Purine Libraries

C1.1.4 Substituent Design

C1.1.5 Additivity of the Biological Effects

C1.1.6 Browser of Substituents at the C-2 Position

C1.1.7 Browser of Substituents at the C-6 Position

C1.1.8 Successive Rounds

C1.1.9 Library Results

C1.2 Case Study-2 : DHFR Inhibitors

C1.2.1 Diaminopyrimidines DHFR Inhibitors

C1.2.2 Soluble Diaminopyrimidine Scaffold

C1.2.3 Design of 2,4-Diaminopyrimidine Library

C1.2.4 Structure-Based Design Strategy

C1.2.5 3D Structural Data Available

C1.2.6 2,4-Diaminopyrimidine Anchorage to DHFR

C1.2.7 Docking of the Virtual Library

C1.2.8 Selection and Synthesis

C1.2.9 Biological Tests

C1.2.10 Detailed Analysis of Binding Mode

C1.2.11 Enantiomers with Different Activities

C1.2.12 Binding Mode and Absolute Stereochemistry

C1.2.13 Diversity-Based Strategy

C1.2.14 Selection Based on Diversity of Pair Overlaps

C1.2.15 Selection of Molecules and Biological Tests

C1.2.16 Structure-Based vs. Diversity-Based Strategy

C1.2.17 Efficiency of the Structure-Based Selection

C1.2.18 Summary

C1.2.19 What can we Learn from this Study ?

C1.3 Case Study-3 : Aminothiazole Libraries

C1.3.1 Design of Diverse and Focused Libraries

C1.3.2 Steps in Library Design Process

C1.3.3 Define Chemical Reaction

C1.3.4 Select Pool of Possible Building Blocks

C1.3.5 Refine List of Building Blocks

C1.3.6 Library Enumeration C1.3.7 Reaction-Based Enumeration

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C1.3.8 Fragment-Based Enumeration

C1.3.9 Properties Profiling of the Virtual Library

C1.3.10 Simple Property Profiling

C1.3.11 Profiling of Knowledge-Based Properties

C1.3.12 Analysis of the Diversity of the Virtual Library C1.3.13 Optimal Subset of the Virtual Library for Synthesis

C1.3.14 Frequency Analysis Method

C1.3.15 Advanced Frequency Analysis

C1.3.16 Example of Advanced Frequency Analysis

C1.3.17 Multicriteria Optimization

C1.3.18 The Weighted Sum Approach

C1.3.19 Limitation of the Weighted Sum Approach

C1.3.20 Multiple Objective Genetic Algorithms (MOGA)

C1.3.21 MOGA Plot and Pareto Ranking

C1.3.22 Example of Multi-Dimensional Optimization

C1.3.23 MOGA Results

C1.3.24 Expanding one MOGA Solution

C1.4 ADDITIONAL CASE STUDIES

C1.4.1 Additional Case Studies

D. ADME PROPERTIES AND PREDICTIONS

D1. CASE STUDIES IN ADME/TOX PREDICTIONS

D1.1 ADME/Tox Case Study 1: Identification of Non-Genotoxic Carcinogens

D1.1.1 Identification of Non-Genotoxic Carcinogens

D1.1.2 Current ADME/Tox Analyses

D1.1.3 Possible Models for Non-Genotoxic Carcinogens

D1.1.4 Both Receptors Form Heterodimers

D1.1.5 Activation for the Arylhydrocarbon Receptor

D1.1.6 The Responsive Elements of Interaction (1/2)

D1.1.7 The Responsive Elements of Interaction (2/2)

D1.1.8 Binding Analysis of the Arylhydrocarbon Receptor (AhR)

D1.1.9 Ligand Identification of the Arylhydrocarbon Receptor (AhR)

D1.1.10 Induction on the mRNA Level by AhR

D1.1.11 Induction on the Enzyme Level by AhR

D1.1.12 Similar Induction of Enzyme Activity Between Species (1/2)

D1.1.13 Similar Induction of Enzyme Activity Between Species (2/2)

D1.1.14 Examples of Rat Specific Induction of Enzyme Activities D1.1.15 Examples of Human Specific Induction of Enzyme Activities

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D1.1.16 Conclusion

D1.1.17 Outcome of this Testing

D1.2 ADME/Tox Case Study 2: Interpretation of Toxicology from an ADMETStandpoint

D1.2.1 Case Studies Presented Here

D1.2.2 The Action of a Drug

D1.2.3 Reasons for Species Specific Responses

D1.2.4 Example-1: Differences in Metabolism

D1.2.5 Different Metabolism of the two Analogs

D1.2.6 Ketoconazole Binding

D1.2.7 Desacetyl-Ketoconazole Binding

D1.2.8 Example-2: Differences in Rate of Metabolism

D1.2.9 PK /PD Model of Response

D1.2.10 Origin of the Hepatotoxicity of Procicromil in Dog D1.2.11 Toxicity due to Different Plasma Clearance Values

D1.2.12 Example-3: Differences in Receptor Affinity

D1.2.13 Affinity for Cardiac Na+/K+ ATPase (1/2)

D1.2.14 Affinity for Cardiac Na+/K+ ATPase (2/2)

D1.2.15 Interpretation of Toxicology from Animal Data

D1.2.16 Interpretation of Toxicology from Human Data

D1.3 ADME/Tox Case Study 3: Drug Withdrawals due to Toxicity

D1.3.1 Drug Failures, Lessons and Learnings for the Future

D1.3.2 Three Types of Drug Withdrawals

D1.3.3 Type A

D1.3.4 Type B

D1.3.5 Type C

D1.3.6 Type D

D1.3.7 Table of Drug Withdrawals from 1980

D1.3.8 Type A1 Drug Withdrawals

D1.3.9 Alosetron

D1.3.10 Cerivastatin

D1.3.11 Flosequinan

D1.3.12 Encainide

D1.3.13 Rofecoxib

D1.3.14 Lessons from Withdrawals due to Primary Pharmacology

D1.3.15 A Broad Spectrum of Drugs

D1.3.16 Impact on Decisions in Drug Discovery

D1.3.17 Type A2 Drug Withdrawals

D1.3.18 Fenfluramine and Dexfenfluramine (1/2)

D1.3.19 Fenfluramine and Dexfenfluramine (2/2)

D1.3.20 Rapacuronium

D1.3.21 Astemizole, Cisapride, Grepafloxacin and Terfenadine (1/2)

D1.3.22 Astemizole, Cisapride, Grepafloxacin and Terfenadine (2/2)

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D1.3.23 Mibefradil

D1.3.24 Lessons from Withdrawals Due to Secondary Pharmacology

D1.3.25 Impact on Discovery Screening Programs

D1.3.26 Type B and C Toxicity Drug Withdrawals (1/4)

D1.3.27 Type B and C Toxicity Drug Withdrawals (2/4) D1.3.28 Type B and C Toxicity Drug Withdrawals (3/4)

D1.3.29 Type B and C Toxicity Drug Withdrawals (4/4)

D1.3.30 Lessons Learned from Type B/C Toxicity

D1.3.31 Importance of Dose in B and C Toxicity

D1.3.32 Type D Toxicity Drug Withdrawals

D1.3.33 Thalidomide

D1.3.34 Balancing Benefit / Risk

D1.3.35 Benefit Analyses for Antidepressants

D1.3.36 Monitoring

E. STRUCTURE-BASED DESIGN

E1. CASE STUDIES IN STRUCTURE-BASED DESIGN

E1.1 Case Study-1 : Phenyl Imidazoles

E1.1.1 Phenyl-Imidazoles Inhibit Cytochrome P450

E1.1.2 Simple Consideration: Shape Similarity

E1.1.3 Perhaps Binding Elements are more Complex ?

E1.1.4 The Structure-Based Answer

E1.1.5 Phenyl-Imidazole Browser

E1.1.6 Limitations of Chemical Intuition

E1.2 Case Study-2 : BACE-1 Inhibitors

E1.2.1 BACE-1 Inhibitors

E1.2.2 Screening the J&J Corporate Compound Collection

E1.2.3 Structural Determinants of the Biological Activity of 1

E1.2.4 X-ray Structure of the Complex of 1 with BACE-1

E1.2.5 Flap Flexibility in Aspartyl Proteases

E1.2.6 Compound with Increased Folding Capability

E1.2.7 How to Gain Additional Binding

E1.2.8 Design of a More Potent Inhibitor

E1.2.9 X-Ray Structure of the Complex with 3a

E1.2.10 Pharmacological Action of Compound 3a

E1.2.11 Important Structural Determinants for Binding

E1.2.12 Summary

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E1.3 Case Study-3 : Factor Xa Inhibitors

E1.3.1 Therapeutic Utility of Factor Xa Inhibitors

E1.3.2 DX-9065a : a Factor Xa Inhibitor

E1.3.3 Complex Between Factor Xa and DX-9065a E1.3.4 Analysis of the Factor Xa and DX-9065a Complex (1/4)

E1.3.5 Analysis of the Factor Xa and DX-9065a Complex (2/4)



E1.3.8 Role of the Carboxylic Acid in Selectivity (1/3)



E1.3.11 Initial Inhibitor Design

E1.3.12 Design (step 1): Structural Moiety for Pocket S1

E1.3.13 Phenyl-Amidine Entered into the S1 Pocket

E1.3.14 Phenyl-Amidine Oriented in Lowest Energy Orientation

E1.3.15 Design (step 2): Structural Moiety for Pocket S4

E1.3.16 Phenyl Ring Introduced in Pocket S4

E1.3.17 Phenyl Substituted with an Amidine

E1.3.18 Stacking Interaction of Phenyl-Amidine with Trp-215

E1.3.19 Phenyl-Amidine Orientation

E1.3.20 Design (step 3): Design of the Spacer

E1.3.21 Phenyl-Amidine Groups in their Preferred Orientations

E1.3.22 Spacer with three Atoms

E1.3.23 Candidate Prototype in the Catalytic Site

E1.3.24 Design (step 4): Positioning of the Carboxylate

E1.3.25 Discovery of a Lead Compound

E1.3.26 Optimization of the Designed Series

E1.3.27 Interaction of Compound 21 with Factor Xa

E1.3.28 Finding an Optimal Spacer

E1.4 Case Study-4 : Kinase Inhibitors

E1.4.1 Pyrrolo-Pyrimidine & Quinazoline EGF-R Inhibitors

E1.4.2 Novartis and Parke-Davis Opposite Binding Models

E1.4.3 Controversy: Novartis & Parke-Davis Binding Modes E1.4.4 Parke-Davis Analyses

E1.4.5 Novartis Analyses

E1.4.6 X-ray Structure of ATP Bound to a Kinase

E1.4.7 Binding Mode of ATP

E1.4.8 Binding Mode of Staurosporine

E1.4.9 Homology Model of EGF-R Catalytic Site

E1.4.10 From Staurosporine to Pyrrolo-pyrimidine

E1.4.11 The Novartis Binding Mode of Pyrrolo-pyrimidine

E1.4.12 The Pyrrole Ring in the Large Pocket

E1.4.13 The Pyrrole Ring Pointing Towards the Sugar Pocket E1.4.14 Parke-Davis Analyses the Quinazoline Scaffold

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E1.4.15 Additional SAR Analyses made by Parke-Davis

E1.4.16 Parke-Davis Model of the Quinazoline Analogs

E1.4.17 Specificity Observed in EGF-R Kinase Inhibition

E1.4.18 Anilino Towards the Sugar Pocket not Reasonable

E1.4.19 Parke-Davis Model Consistent with Observed SAR E1.4.20 Binding Mode of the Pyrrolo-Pyrimidine Series

E1.4.21 Binding Mode of the Quinazoline Series

E1.4.22 What is the Correct Solution?

E1.4.23 Ligand Observed with a Novartis Binding Mode

E1.4.24 Alignment with the Novartis Model

E1.4.25 Ligand Observed with a Parke-Davis Binding Mode

E1.4.26 Alignment with the Parke-Davis Model

E1.4.27 X-Ray Resolution of Tarceva Bound to EGF-R Kinase

E1.4.28 Conclusion

E1.5 ADDITIONAL CASE STUDIES

E1.5.1 Additional Case Studies

E2. CASE STUDIES OF DOCKING IN DRUG DISCOVERY

E2.1 Case Study 1 : Pyrimidin-4-yl-ureas for Kinase Inhibition

E2.1.1 Inhibitor Active on Several Protein Kinases

E2.1.2 Structural Determinants for the Activity

E2.1.3 Correlation with the Volume of Gate Keeper Residue

E2.1.4 Outcome of this Study

E2.2 Case Study 2 : Inhibition of CHK1

E2.2.1 The CHK1 Kinase

E2.2.2 The Indazole Series

E2.2.3 Binding Mode of the Indazole Core E2.2.4 Binding Modes of the Potent Indazole Analog

E2.2.5 Pocket may Help for Selectivity

E2.2.6 Overlay with Other Chk1 Inhibitors

E2.2.7 Structure-Based Screening of Chk1 Inhibitors

E2.2.8 Hits Identified by Virtual Screening

E2.2.9 X-Ray Structures of Four Virtual Screening Hits

E2.2.10 Binding Modes Predicted for Other Five Hits

E2.2.11 Outcome of this Study

E2.3 Case Study 3 : Thrombin Inhibitors

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E2.3.1 Two Methods of Virtual Screening

E2.3.2 Combining Structure-Based and Ligand-Based VS

E2.3.3 Screening Protocol

E2.3.4 Steps of the Docking Treatment

E2.3.5 Specificity Pockets in Thrombin E2.3.6 Development of the Hybrid Approach

E2.3.7 Inhibition Assays of Top-Scoring Compounds

E2.3.8 Analysis of the Binding Mode of Compound 1

E2.3.9 Binding Mode Compared with Known Inhibitors

E2.3.10 What was Learned in this Test Study ?

E2.3.11 Analyzing Top Ranked Compounds

E2.3.12 Limitations of Scoring Functions

E2.4 Case Study 4 : Salicylamide Renin Inhibitor

E2.4.1 Search for New Scaffold in Renin Inhibition E2.4.2 3D Analyses

E2.4.3 Preferred Location of Phenyl Ring in Pocket P3

E2.4.4 Docking Experiment

E2.4.5 Results of the Docking

E2.4.6 Search for an Optimal Spacer

E2.4.7 The Salicylamide Lead

E2.4.8 Predictions Confirmed by X-Ray Study

E2.4.9 Browser of Salicylamide Inhibitor

E2.4.10 Optimization of the Salicylamide Series

E2.4.11 Summary E2.4.12 Lead Hopping

E2.5 Case Study 5 : Inhibition of Human Neutrophil Elastase

E2.5.1 Inhibition of Human Neutrophil Elastase

E2.5.2 Sesquiterpene Lactones

E2.5.3 Studies on 17 Sesquiterpene Lactones

E2.5.4 Docking Studies

E2.5.5 Docking Protocol

E2.5.6 Results of the Docking Studies

E2.5.7 Elucidation of the Mode of Action

E2.5.8 Docking Results of Melampolides 2 and 4

E2.5.9 Docking Results of Podachaenin 14

E2.5.10 Docking Results of Germacranolide 8

E2.5.11 Structural Determinants for Binding to HNE

E2.5.12 Summary

E2.6 ADDITIONAL CASE STUDIES

E2.6.1 Additional Case Studies

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F. CHEMINFORMATICS

F1. CASE STUDIES IN 3D DATABASE SEARCHING

F1.1 Case Study-1 : Ligands of the Dopamine D3 Receptor

F1.1.1 Reference Compounds

F1.1.2 Pharmacophore Model

F1.1.3 Model of the Dopamine D3 Receptor

F1.1.4 Residues Involved in the Binding

F1.1.5 Combined Pharmacophore and Structure-Based Searching

F1.1.6 Results of the 3D Searching

F1.1.7 Summary

F1.1.8 Browser of Dopamine D3 Receptor Ligands

F1.2 Case Study-2 : Non-Peptidic Cyclophilin Ligands

F1.2.1 Reference Compound: Cyclosporin A

F1.2.2 The Bioactive Conformation of Cyclosporin A


F1.2.4 Results of 3D Searching

F1.2.5 Superposition of the Hit with Cyclosporin-A

F1.2.6 Optimization of Initial Hit F1.2.7 Browser of Non-Peptidic Cyclophilin Ligands

F1.3 Case Study-3 : Motilin Receptor Antagonists

F1.3.1 Motilin Receptor Antagonists

F1.3.2 Motilin Receptor and Motilin Peptide

F1.3.3 Structural Analyses on Motilin

F1.3.4 Analyses of Motilin Folding

F1.3.5 Bioactive Conformation of Motilin

F1.3.6 Biologically Relevant Residues of Motilin

F1.3.7 The Motilin Pharmacophore

F1.3.8 RWJ-64583: a Trisubstituted Cyclopentene Lead

F1.3.9 The Three-point Pharmacophore and RWJ-64583

F1.3.10 Optimization of the Initial Lead Molecule

F1.3.11 Mimicking the Phe-5 of Motilin

F1.4 Case Study-4 : Inhibitors of HIV-1 Protease

F1.4.1 HIV-1 Protease Inhibition

F1.4.2 The Peptide Problem

F1.4.3 Database Searching for Non-Peptidic Scaffolds

F1.4.4 The Terphenyl Derivative Hit

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F1.4.5 Analysis of the Content of the Hit

F1.4.6 Replacing Cyclohexanone by a 7-Membered Ring

F1.4.7 Problem of the 6-membered Ring

F1.4.8 Optimal Framework: 7-membered Cyclic Urea

F1.4.9 Design of Cyclic Urea Scaffold F1.4.10 XK-263 is a Non-Peptidic Mimic of A-77003

F1.4.11 Summary

F1.5 Case Study-5 : Non-Sugar Antagonists of Selectin

F1.5.1 Reference Compound

F1.5.2 Initial SAR Analyses


F1.5.4 Results of 3D Searching

F1.5.5 Optimization of the Diphenyl Ether Hit

F1.5.6 Optimization of the Diphenyl Ether Hit F1.5.7 Optimization of the Diphenyl Ether Hit

F1.5.8 Summary

F1.5.9 Browser of Selectin Antagonists

F1.6 Case Study-6 : Dopamine Transporter Inhibitors

F1.6.1 The Dopamine Transporter Target

F1.6.2 Methodology: 3D Database Searching

F1.6.3 First Pharmacophore

F1.6.4 3D Searching Results with the First Pharmacophore

F1.6.5 Piperidinol Hit

F1.6.6 Optimization of the Piperidinol Hit

F1.6.7 Quinuclidine Hit

F1.6.8 Optimization of the Quinuclidine Hit

F1.6.9 Phenyl-4 Piperidine Hit

F1.6.10 Optimization of the Phenyl-4 Piperidine Hit

F1.6.11 Challenging the First Pharmacophore

F1.6.12 Structural Analyses of the Quinuclidine Hit

F1.6.13 Modeling Analyses: C=O Not Necessary!

F1.6.14 Browser Associated to the First Pharmacophore

F1.6.15 What Can Be Learned So Far?

F1.6.16 Second Pharmacophore

F1.6.17 Characteristics of the Second Pharmacophore

F1.6.18 3D Searching with the Second Pharmacophore

F1.6.19 Optimization of the Pyrrolidine Hit

F1.6.20 What Can Be Learned So Far?

F1.6.21 Browser Associated to the Second Pharmacophore

F1.6.22 Third Pharmacophore

F1.6.23 Bioactive Form of Mazindol

F1.6.24 Characteristics of the Third Pharmacophore

F1.6.25 3D Searching with Third Pharmacophore

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F1.6.26 Browser Associated to the Third Pharmacophore

F1.6.27 Fourth Pharmacophore

F1.6.28 Aligning Low Energy Conformers

F1.6.29 Characteristics of the Fourth Pharmacophore

F1.6.30 3D Searching with the Fourth Pharmacophore F1.6.31 Optimization of the Substituted Pyridine Hit

F1.6.32 Browser Associated to the Fourth Pharmacophore

F1.6.33 Summary

F1.7 ADDITIONAL CASE STUDIES

F1.7.1 Additional Case Studies

G. LIGAND-BASED DESIGN

G1. CASE STUDIES IN LIGAND-BASED DESIGN

G1.1 Case Study-1 : Aromatase Inhibitors

G1.1.1 Therapeutic Utility of Aromatase Inhibitors

G1.1.2 Reference Set of Aromatase Inhibitors

G1.1.3 Pharmacophore for Aromatase Inhibitors (1/3)



G1.1.6 The Design of a New Inhibitor of Aromatase

G1.1.7 Browser of Aromatase Inhibitors

G1.2 Case Study-2 : Substance P Antagonists

G1.2.1 Therapeutic Utility of Substance P Antagonists

G1.2.2 Reference Set of Substance P Antagonists

G1.2.3 Pharmacophore for Substance P Antagonists

G1.2.4 Origin of the Poor Activity of SP4

G1.2.5 Constrained Boat Conformation of CP96345

G1.2.6 The Design of a Potent Substance P Antagonist

G1.2.7 The Superimposition of CP96345 and CP99994

G1.2.8 Browser of Substance P Antagonists

G1.3 Case Study-3 : Tricyclic Antidepressants

G1.3.1 Mode of Action of Tricyclic Antidepressants

G1.3.2 Reference Set of Antidepressant Molecules

G1.3.3 Invalidation of the "Butterfly" Model G1.3.4 Pharmacophore for Antidepressants

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G1.3.5 Browser for Antidepressant Agents

G1.3.6 The Design of RU-22249

G1.3.7 Browser for Antidepressant Agents

G1.4 Case Study-4 : Morphinan Analgesics

G1.4.1 Importance of Energies in Ligand-Based Design

G1.4.2 Morphinan and D-nor Morphinan Alignment

G1.4.3 Conformational Analysis of Morphinan

G1.4.4 Conformational Analysis of D-nor Morphinan

G1.4.5 A Rationale for Explaining the Activities Observed

G1.4.6 Morphinan: Validation and Design

G1.4.7 Preferred Conformer of Active Enantiomer

G1.4.8 Preferred Conformer of Inactive Enantiomer

G1.4.9 Restoring Activities to the Inactive Analog?

G1.4.10 Morphinan Browser G1.4.11 What We Can Learn From The Morphinan Example

G1.5 ADDITIONAL CASE STUDIES

G1.5.1 Additional Case Studies

H. QSAR AND CHEMOMETRICS

H1. CASE STUDIES IN QSAR AND 3D-QSAR

H1.1 Case Study-1 : QSAR of Capsaicin Analogs

H1.1.1 Example of Capsaicin Analogs

H1.1.2 Relevant Descriptors of Capsaicin Analogs

H1.1.3 The Capsaicin Study Table

H1.1.4 Graphical Analysis of Capsaicin Analogs

H1.1.5 Deriving a QSAR Linear Equation

H1.1.6 Experimental vs. Calculated Values (1/2)

H1.1.7 Experimental vs. Calculated Values (2/2)

H1.1.8 Calculating r for the Capsaicin analogs

H1.1.9 t-test for the Capsaicin Analogs

H1.1.10 F-test for a Series of the Capsaicin Analogs

H1.1.11 The QSAR Equation for the Capsaicin Analogs

H1.1.12 Predicting the Activities of Unknown Compounds

H1.2 Case Study-2 : 3D-QSAR of Steroid Analogs

H1.2.1 The Reference Compounds

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H1.2.2 The Biological Data

H1.2.3 Molecular Alignment

H1.2.4 CoMFA Field Calculations

H1.2.5 CoMFA and PLS Results vs. Classical QSAR

H1.2.6 Steric CoMFA Map for Binding to TBG H1.2.7 Electrostatic CoMFA Map for Binding to TBG

H1.2.8 CBG Affinities of New Steroids

H1.2.9 Predicting the CBG Affinities of New Steroids

Molecular Conceptor 2.16Synergix ltd. 1996-2012

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