Computer-aided drug design : methods and applications / edited by Thomas J. Perun, C.L. Propst.

Format:

Book

Contributor:

Perun, Thomas J.

Propst, C. L. (Catherine Lamb), 1946-

Language:

English

Subjects (All):

Drugs--Design--Data processing.

Drugs.

Computer-aided design.

Chemistry, Pharmaceutical.

Computers.

Models, Molecular.

Drugs--Design.

Medical Subjects:

Chemistry, Pharmaceutical.

Computers.

Models, Molecular.

Physical Description:

xii, 493 pages : illustrations ; 24 cm

Place of Publication:

New York : Marcel Dekker, [1989]

Summary:

Covering both methods and applications, this state-of-the-art volume focuses on computational and experimental techniques for computer-aided drug design (CADD). It discusses what pitfalls are encountered and how they can be overcome, and provides recent examples of successes and failures of various approaches. Completely referenced with 900 bibliographic citations of the literature -- including 1988 data -- and richly illustrated with drawings, tables, and black and white and color photographs, Computer-Aided Drug Design compares CADD to classical empirical medicinal chemical methodology ... discusses modern molecular modeling and molecular dynamics methods ... describes very new NMR techniques ... considers the use of x-ray crystal structures to design enzyme inhibitors ... offers never-before-published material on problems involved in the interpretation of enzyme inhibitor kinetics ... details the design of new angiotensin-converting enzyme inhibitors, renin inhibitors, antiviral agents, conformationally constrained neuroreceptor agonists, and antagonists ... plus more. An excellent reference for scientists involved in all phases of drug research and development, this book is also a valuable text for graduate students in pharmacology, medicinal chemistry, chemistry, and molecular biology.

Contents:

II. How Drugs Are Discovered 2

III. The Basics of Mechanistic Drug Design 4

IV. Important Techniques for Drug Design 11

Methods

2. Uses of Computer Graphics in Computer-Assisted Drug Design / T. J. O'Donnell 19

II. Computer Graphic Displays 20

III. Computed Molecular Models 25

IV. Molecular Modeling Systems for Drug Design 31

V. Uses of Computer-Assisted Drug Design 34

VI. Extending Molecular Modeling 43

3. Theoretical Aspects of Drug Design: Molecular Mechanics and Molecular Dynamics / Stanley K. Burt, Donald Mackay, Arnold T. Hagler 55

II. Potential Energy Function 58

III. Nonbonded Energy Terms 59

IV. Electrostatic Energy (V[subscript es])

Theoretical Considerations 62

V. Hydrogen Bonds 67

VI. Energy Minimization 70

VII. Applications of Theoretical Techniques to Drug Design 72

VIII. Future Directions 85

4. X-Ray Crystallography and Drug Design / Donald J. Abraham 93

III. Examples of Crystallographic Studies 104

IV. Hemoglobin as a Model System for Drug-Protein Interactions and Drug Design: Antisickling and Antiischemic Agents 114

5. Approaches to Drug Design Using Nuclear Magnetic Resonance Spectroscopy / Stephen W. Fesik 133

II. Conformational Analysis 134

III. Small Molecule-Large Molecule Interactions 157

IV. Enzyme Reactions 168

6. Enzyme Kinetics in Drug Design: Implications of Multiple Forms of Enzymes on Substrate and Inhibitor Structure-Activity Correlations / Daniel H. Rich, Dexter B. Northrop 185

I. Introduction: Evidence for Multiple Forms of Enzyme 186

II. Derivation of a General Model for Enzyme-Substrate Interaction 188

III. Slow-Binding and Tight-Binding Enzyme Inhibitors 199

IV. Effects of Multiple Forms on Enzyme Inhibition: Strategies of Experimental Design and Guides for Evaluating Kinetic Data 222

Applications

7. Computer-Aided Design and Evaluation of Angiotensin-Converting Enzyme Inhibitors / David G. Hangauer 253

II. Design of Captopril with the Aid of a Conceptual Model for Angiotensin-Converting Enzyme 254

III. Molecular Mechanics-Aided Design of Conformationally Restricted Captopril Analogs 260

IV. Molecular Mechanics-Aided Design of Conformationally Restricted Enalaprilat Analogs 264

V. Computer-Aided Design of Cilazapril 271

VI. Mapping the Angiotensin-Converting Enzyme Active Site from a Conformational Analysis of Diverse Inhibitors 277

VII. Thermolysin as a Model for Angiotensin-Converting Enzyme 281

8. Role of Computer-Aided Molecular Modeling in the Design of Novel Inhibitors of Renin / Giorgio Bolis, Jonathan Greer 297

II. Modeling of the Receptor and Substrate 301

III. Working with the Receptor-Inhibitor Model 306

9. Inhibitors of Dihydrofolate Reductase / Lee F. Kuyper 327

II. The Enzyme 328

III. Enzyme-Inhibitor Interactions 338

IV. Inhibitor Design 346

10. Approaches to Antiviral Drug Design / Thomas J. Smith 371

II. Rhinovirus as a Drug Receptor 376

III. Designing Antiviral Drugs 380

11. Conformation Biological Activity Relationships for Receptor-Selective, Conformationally Constrained Opioid Peptides / Victor J. Hruby, B. Montgomery Pettitt 405

III. Design of Conformationally Constrained Delta Opioid Receptor-Selective Peptides 417

IV. Design of Conformationally Constrained [mu] Opioid Receptor-Selective Peptides 441

V. Problems and Prospects for Rational Design of Receptor-Selective Peptides 450

12. Design of Conformationally Restricted Cyclopeptides for the Inhibition of Cholate Uptake of Hepatocytes / Horst Kessler, A. Haupt, Martin Will 461

II. Uptake of Organic Substrates by Hepatocytes 463

III. Structure-Activity Relationships for Hepatocellular Cholate Uptake Inhibition 465

IV. Possible Applications 478.

Notes:

Includes bibliographies and index.

ISBN:

082478037X

OCLC:

18948317