Molecular Structure Description: Kier; Hall: 9780124065550: Book: Science: eCampus.com

The entire thrust of industrial drug research is now directed toward the use of predictive methods and strategies to reduce the number of compounds made and tested. Furthermore, these theoretical/computational methods are increasingly part of a general approach to chemical problems. Among non-empirical structure indices, the electrotopological state of atoms in a molecule is a new paradigm, providing a descriptor of intermolecular interactions at submolecular sights that is easy to calculate and information-rich. One of the authors (Hall) has included the E-state in his widely used MOLCONN computer program. Tripos has incorporated this index as an optional module for structure-activity analyses using a new Web-based tool called CHEMenlighten.

Key Features
* Reflects the rich experience of the authors as developers of the E-state method
* Provides a first-hand account of the origins and use of this new paradigm
* Includes E-Calc software on CD-ROM for hands-on experience with the method
* Offers strategies for drug design

Molecular Structure Description describes a new computer-based approach to calculating meaningful numbers for the different parts of a molecule. These numbers carry information about the important contributions of parts of molecules to their properties as potential drugs. This information is of great value in predicting what molecules to make that would have the best possibility of being biologically active.It plays a vital role in modern scientific techniques such as database management, combinatorial robotics synthesis methods, similarity discovery, and molecular modeling.

Foreword

xiii

(4)

Preface

xvii

1 Introduction

(12)

I. The General Problem

(2)

II. What Is Structure?

(3)

A. The Chemical Graph

(1)

B. Structure and Substructure

(1)

III. Aspects of Atom-Level Description

(3)

A. The Electronic/Steric Duality of Structure Description

(1)

B. The Localization of Structure Description

(1)

C. The Dimensionality Question

(1)

IV. Summary

(1)

V. A Look Ahead

(1)

References

(4)

2 The Electrotopological State

(24)

I. The Molecule as a Complex System

(1)

II. Atom Information Fields

(1)

III. The Intrinsic State of an Atom

(2)

IV. The Graph Representation of a Molecule

(1)

V. The Atom Representation

(3)

A. The Delta Values

(1)

B. The Electronic Information in the Delta Values

(2)

VI. The Intrinsic State Algorithm

(1)

VII. Higher Quantum-Level Atoms

(2)

VIII. Field Influences on the Intrinsic State

(1)

IX. Sample Calculations

(4)

X. Influence of Structure Change on E-State Values

(4)

XI. Calculation Exercises

(4)

A. The Delta Parameter

(1)

B. The Intrinsic State, I

(1)

C. The E-State Value, S

(1)

D. The Direct Path Used in the (Delta) I Calculations

(1)

E. Large Molecule Calculations

(2)

XII. Summary

(1)

XIII. A Look Ahead

(1)

References

(2)

3 Significance and Interpretations of the E-State Indices

(20)

I. The Intrinsic State Values

(2)

A. The Carbon sp^(3) Hydrides

(1)

B. Heteroatoms

(1)

II. Comparison of the E-State Values with Other Indices

(5)

A. Estimated Partial Charges

(1)

B. Taft (Sigma)* Parameters

(1)

C. Rekker f Values

(2)

D. Comparison of Lipophilic, Steric, and Electronic Parameters

(1)

III. The E-State Spectrum Significance

(4)

IV. The E-State and Free Valence

(6)

A. Comparison of Free Valence and E-State Values

(1)

B. Free Valence Indices for Unspecified Atoms

(5)

V. Summary

(1)

VI. A Look Ahead

(1)

References

(3)

4 Extended Forms of the E-State

(20)

I. Specific Consideration of Hydrogen

(5)

A. The Hydrogen-Equivalent Model

(1)

B. The Partition Model

(1)

C. A Hydrogen Intrinsic State Using an X-H Model

(2)

D. Electronegativity-Based Hydrogen E-State

(1)

II. The E-State as a Three-Dimensional Field

(3)

A. Three-Dimensional QSAR

(1)

B. Calculation of E-State Fields

(1)

C. Display of 3-D E-State Fields

(1)

D. Advantages of Field Representation of E-State in QSAR

(1)

E. Representative Studies

(1)

III. Molecular and Group Polarity Index

(2)

IV. The Atom-Type Indices

(7)

A. Atom-Type Classification Scheme

(5)

B. Sample Calculation

(1)

C. Significance of the Atom-Type E-State Values

(1)

D. Atom-Type Hydrogen E-State Indices

(1)

V. Summary

(1)

VI. A Look Ahead

(1)

References

(3)

5 Strategies for Use of the E-State

(26)

I. Experimental Design

(3)

II. Preliminary Data Analysis

(2)

A. The Range of Variables: Variance

(1)

B. Independence of Variables

(1)

C. Eigenvalues and Principal Components

(1)

D. Data Plots: Activity and Structure Descriptors

(1)

E. Overall Perspective

(1)

III. Topological Superposition Strategy

(1)

IV. Data Selection and Manipulation

(3)

A. Form of Activity Quantitation

(1)

B. Indefinite Activity Expression

(1)

C. Uncertain Degree of Ionization

(1)

D. Data from Several Sources

(1)

E. Departure from a Protocol

(1)

F. Stereoisomers

(1)

G. Aberrant Parameters

(1)

H. Unstable Molecules

(1)

I. Use of Log Activities

(1)

V. Structure Data Input

(1)

VI. Calculation of Tautomers and Equivalent Atoms

(2)

VII. Consideration of Types of Indices

(1)

VIII. Use of Orthogonalized Indices: Antagonism of Adrenalin by 2-Bromo-2-phenalkylamines

(4)

A. Independence of Structure Descriptors

(1)

B. Antagonism of Adrenalin by 2-Bromo-2-phenalkylamines

(3)

IX. Illustration of the Partial Least Squares Method: Flavone Derivatives as HIV-1 Integrase Inhibitors

(3)

A. Flavone Derivatives as HIV-1 Integrase Inhibitors

(2)

B. Partial Least Squares Results

(1)

X. Artificial Neural Networks: Solubility of HIV Reverse Transcriptase Inhibitors

(3)

A. Solubility of Inhibitors

(1)

B. Neural Network Results

(1)

XI. Summary

(1)

XII. A Look Ahead

100

(1)

References

100

(3)

6 Database Applications: Molecular Similarity and Diversity

103

(40)

I. Molecular Similarity

103

(3)

II. The E-State Information Field

106

(9)

A. The Intrinsic State

106

(1)

B. A Hyperspace of E-State Indices

107

(8)

III. Characterization of E-State Space

115

(8)

A. Hydrocarbons

116

(1)

B. Molecules Containing Heteroatoms

117

(1)

C. Generalizations

117

(1)

D. Drug Molecules

118

(5)

IV. Functional Group Description in Parameter Space

123

(1)

V. The Quantitation of Molecular Fragments

123

(6)

A. Method

124

(5)

B. Value of the Fragment Search Approach

129

(1)

VI. Organization of Database Subsets

129

(5)

VII. Diversity

134

(1)

VIII. Virtual Screening

135

(4)

A. Database Evaluation

136

(1)

B. Similarity Analysis

137

(1)

C. QSAR Analysis

137

(1)

D. Pharmacophore Identification

138

(1)

E. Final Comments

139

(1)

IX. Exercises

139

(1)

X. Summary

140

(1)

XI. A Look Ahead

140

(1)

References

141

(2)

7 Structure-Activity Studies: Atom-Level Indices

143

(26)

I. The Structure-Activity Paradigm

143

(1)

II. Inhibition of Monoamine Oxidase by Hydrazides

143

(4)

III. Odor Threshold of Alkylpyrazines

147

(1)

IV. Xanthine Inhibitors of Adenosine A(1)

148

(3)

V. Benzimidazoles as Influenza Virus Inhibitors

151

(1)

VI. Binding of Barbiturates to Cyclodextrin

152

(3)

VII. Imidazole Inhibitors of Thromboxane Synthase

155

(1)

VIII. Binding of Salicylamides

156

(2)

IX. Binding of Corticosteroids

158

(5)

X. Exercises

163

(2)

XI. Summary

165

(1)

XII. A Look Ahead

165

(1)

References

165

(4)

8 Structure-Activity Studies: Mixed Indices

169

(34)

I. Analyses with a Mixed Set of Indices

169

(1)

II. Reaction of the OH Radical with Chlorofluorocarbons

170

(2)

III. 5-HT(2) Binding of Phenylisopropylamines

172

(1)

IV. Opiate Receptor Activity of Fentanyl-like Compounds

173

(2)

V. E-State and Bimolecular Encounter Parameters

175

(3)

A. Primary Amine Boiling Points

176

(1)

B. Alcohol Boiling Points

177

(1)

VI. Dopamine Receptor Ligands

178

(2)

VII. Carboquinones as Antileukemic Agents

180

(4)

VIII. Toxicity of Amide Herbicides

184

(5)

IX. Aqueous Solubility of Drug Molecules Using Artificial Neural Networking

189

(2)

X. Inhibition of Monoamine Oxidase by Phenethylamines: Relation to Free Valence

191

(3)

XI. Direct QSAR Modeling of Percent Effect Data

194

(5)

A. Chloromethanesulfonamide Acaricidal Activity against Citrus Red Mites

195

(1)

B. Neural Network Analysis

195

(3)

C. Concluding Remarks

198

(1)

XII. Summary

199

(1)

XIII. A Look Ahead

199

(1)

References

199

(4)

9 Structure-Activity Studies: Atom-Type Indices

203

(16)

I. Use of Atom-Type Indices

203

(1)

II. Toxicity of Substituted Benzenes to Fathead Minnows

203

(5)

III. Boiling Point and Critical Temperature of a Set of Heterogeneous Compounds

208

(6)

A. Boiling Point

209

(2)

B. Critical Temperature

211

(2)

C. Concluding Remarks on Boiling Point and Critical Temperature

213

(1)

IV. Boiling Point of a Set of 372 Polychloroalkanes, Alcohols, and Alkanes

214

(3)

V. Summary

217

(1)

VI. A Look Ahead

217

(1)

References

217

(2)

10 Future Directions of E-State Studies

219

(22)

I. Group E-State Indices

219

(2)

II. An Iterative E-State

221

(1)

III. Higher Dimensional E-State Calculations

222

(5)

A. cis-trans Isomers

222

(2)

B. Conformers

224

(2)

C. Acetylcholine Conformers

226

(1)

IV. Parameterizing the Onium Group

227

(2)

V. E-State Index for Bonds and Bond Types

229

(6)

A. Steps in the Formalism

229

(2)

B. Sample Calculation

231

(3)

C. Application of Bond-Type E-State to Boiling Point

234

(1)

VI. Finale

235

(2)

VII. The Grand Finale

237

(1)

A. Derivation

237

(1)

B. Information

237

(1)

C. Interpretation

238

(1)

D. Illuminations

238

(1)

E. Generality

238

(1)

F. Databases

238

(1)

VIII. A Look Ahead

238

(1)

References

239

(2)

Index

241-245

(4)

E-Calc User's Guide

E-1




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