Computer-Aided Drug Design : Methods and Applications Book

	Preface	v
	Contributors	vii
1.	Introduction to Computer-Aided Drug Design	1
I.	Introduction	2
II.	How Drugs Are Discovered	2
III.	The Basics of Mechanistic Drug Design	4
IV.	Important Techniques for Drug Design	11
V.	Conclusions and Future Perspectives	14
	References	15
	Methods
2.	Uses of Computer Graphics in Computer-Assisted Drug Design	19
I.	Introduction	20
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
	References	52
3.	Theoretical Aspects of Drug Design: Molecular Mechanics and Molecular Dynamics	55
I.	Introduction	56
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
	References	86
4.	X-Ray Crystallography and Drug Design	93
I.	Introduction	94
II.	Methodology	94
III.	Examples of Crystallographic Studies	104
IV.	Hemoglobin as a Model System for Drug-Protein Interactions and Drug Design: Antisickling and Antiischemic Agents	114
V.	Conclusions	122
	References	124
5.	Approaches to Drug Design Using Nuclear Magnetic Resonance Spectroscopy	133
I.	Introduction	133
II.	Conformational Analysis	134
III.	Small Molecule-Large Molecule Interactions	157
IV.	Enzyme Reactions	168
V.	Conclusions and Future Perspectives	172
	References	173
6.	Enzyme Kinetics in Drug Design: Implications of Multiple Forms of Enzymes on Substrate and Inhibitor Structure-Activity Correlations	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
V.	Summary	236
	Appendix 1	237
	Appendix 2	242
	References	244
	Applications
7.	Computer-Aided Design and Evaluation of Angiotensin-Converting Enzyme Inhibitors	253
I.	Introduction	254
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
VIII.	Conclusions	290
	References	292
8.	Role of Computer-Aided Molecular Modeling in the Design of Novel Inhibitors of Renin	297
I.	Introduction	298
II.	Modeling of the Receptor and Substrate	301
III.	Working with the Receptor-Inhibitor Model	306
IV.	Applications and Examples	309
V.	Conclusions	323
	References	324
9.	Inhibitors of Dihydrofolate Reductase	327
I.	Introduction	327
II.	The Enzyme	328
III.	Enzyme-Inhibitor Interactions	338
IV.	Inhibitor Design	346
V.	Conclusions	363
	References	364
10.	Approaches to Antiviral Drug Design	371
I.	Introduction	372
II.	Rhinovirus as a Drug Receptor	376
III.	Designing Antiviral Drugs	380
IV.	Conclusions	400
	References	401
11.	Conformation Biological Activity Relationships for Receptor-Selective, Conformationally Constrained Opioid Peptides	405
I.	Introduction	406
II.	General Considerations	407
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
	References	452
12.	Design of Conformationally Restricted Cyclopeptides for the Inhibition of Cholate Uptake of Hepatocytes	461
I.	General Remarks	461
II.	Uptake of Organic Substrates by Hepatocytes	463
III.	Structure-Activity Relationships for Hepatocellular Cholate Uptake Inhibition	465
IV.	Possible Applications	478
V.	Conclusions	478
	References	480
	Index	485