Molecular Conceptor - Table of Contents

Practical Drug Discovery: Case Studies Last 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) A1.3.4 Analysis of Tarceva Binding to the EGF-R Kinase (2/4) A1.3.5 Analysis of Tarceva Binding to the EGF-R Kinase (3/4) A1.3.6 Analysis of Tarceva Binding to the EGF-R Kinase (4/4) 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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A1.5 Case Study-5 : Carbonic Anhydrase Example

A1.5.1 The Carbonic Anhydrase Protein A1.5.2 Therapeutic Utility of CA Inhibitors A1.5.3 MK-417 is a Potent Inhibitor of CA A1.5.4 Binding of MK-417 with CA Protein (1/5) A1.5.5 Binding of MK-417 with CA Protein (2/5) A1.5.6 Binding of MK-417 with CA Protein (3/5) A1.5.7 Binding of MK-417 with CA Protein (4/5) A1.5.8 Binding of MK-417 with CA Protein (5/5) A1.5.9 S Enantiomer is more Potent than the R A1.5.10 Geometry of Isobutyl Side Chain by X-rays A1.5.11 Axial/Equatorial Orientation of the Side Chain A1.5.12 Bioactive Conformation of MK-417 A1.5.13 Energy Considerations A1.5.14 Results of the Analyses A1.5.15 Optimization of MK-417 A1.5.16 Dorzolamide, a Potent Inhibitor of CA A1.5.17 Complex of CA with Dorzolamide A1.5.18 Binding of Dorzolamide with CA Protein (1/5) A1.5.19 Binding of Dorzolamide with CA Protein (2/5) A1.5.20 Binding of Dorzolamide with CA Protein (3/5) A1.5.21 Binding of Dorzolamide with CA Protein (4/5) A1.5.22 Binding of Dorzolamide with CA Protein (5/5)

A1.6 Case Study-6 : -Lactam Antibiotics

A1.6.1 Antibiotic Activities in the Cephalosporin Series A1.6.2 Stereochemical Hypothesis A1.6.3 Same Stereochemistry in the two Structures A1.6.4 Inactivity not due to a Wrong Stereochemistry A1.6.5 Attempts Towards a Geometrical Interpretation A1.6.6 Flexibility of the Enzyme ? A1.6.7 The Lactam Nitrogen Pyramidality Hypothesis A1.6.8 Deficiency of the Nitrogen Pyramidality Hypothesis A1.6.9 Penem and Carbapenems A1.6.10 Pyramidality of Nitrogen Atom ? A1.6.11 Geometrical Aspects Need to be Reassessed A1.6.12 Bioactive Conformation of Penicillins? A1.6.13 Pseudorotation of the Penam Ring A1.6.14 The two Forms were Found in X-ray Determinations A1.6.15 Revealing Bioactive Conformation of Penicillins A1.6.16 Modeling Analyses A1.6.17 Separation Between Active and Inactive Molecules A1.6.18 Other Beta-Lactam Antibiotic Structures A1.6.19 Browser of Beta-Lactam Antibiotics A1.6.20 Validation and Perspectives

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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) A2.1.15 Modeling the Active Site of ACE (2/4) A2.1.16 Modeling the Active Site of ACE (3/4) A2.1.17 Modeling the Active Site of ACE (4/4) 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 B1.5.4 Biological Tests 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 B1.6.5 Biological Tests 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 B1.7.5 Biological Tests 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) B2.5.3 Losartan as a Mimic of Angiotensin-II (2/5) B2.5.4 Losartan as a Mimic of Angiotensin-II (3/5) B2.5.5 Losartan as a Mimic of Angiotensin-II (4/5) B2.5.6 Losartan as a Mimic of Angiotensin-II (5/5) 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) B2.6.3 Pharmacophore Analysis: CCK-A Antagonists (2/3) B2.6.4 Pharmacophore Analysis: CCK-A Antagonists (3/3) 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) B2.8.3 Mdm2 Bound to p53 Transactivation Domain (2/4) B2.8.4 Mdm2 Bound to p53 Transactivation Domain (3/4) B2.8.5 Mdm2 Bound to p53 Transactivation Domain (4/4) 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

B2.9 ADDITIONAL CASE STUDIES

B2.9.1 Additional Case Studies

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) B3.2.6 SAR, NMR and Modeling of the DPDPE series (2/3) B3.2.7 SAR, NMR and Modeling of the DPDPE series (3/3) B3.2.8 Bioactive Conformation of DPDPE (1/4) B3.2.9 Bioactive Conformation of DPDPE (2/4) B3.2.10 Bioactive Conformation of DPDPE (3/4) B3.2.11 Bioactive Conformation of DPDPE (4/4) 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) B3.5.5 Analysis of the Binding of TFMK (2/4) B3.5.6 Analysis of the Binding of TFMK (3/4) B3.5.7 Analysis of the Binding of TFMK (4/4) 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

B3.6 ADDITIONAL CASE STUDIES

B3.6.1 Additional Case Studies

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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 ADMET Standpoint

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) E1.3.6 Analysis of the Factor Xa and DX-9065a Complex (3/4) E1.3.7 Analysis of the Factor Xa and DX-9065a Complex (4/4) E1.3.8 Role of the Carboxylic Acid in Selectivity (1/3) E1.3.9 Role of the Carboxylic Acid in Selectivity (2/3) E1.3.10 Role of the Carboxylic Acid in Selectivity (3/3) 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 F1.2.3 Pharmacophore Model 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 F1.5.3 Pharmacophore Model 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) G1.1.4 Pharmacophore for Aromatase Inhibitors (2/3) G1.1.5 Pharmacophore for Aromatase Inhibitors (3/3) 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 2.16 Synergix ltd. 1996-2012

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