Chemical Structure-Biological Activity Relationships: Quantitative Approaches (eBook)

Front Cover 2
Chemical Structure–Biological Activity Relationships Quantitative Approaches 4
Copyright Page 5
Table of Contents 6
Preface 12
List of participants 14
PART I: PREDICTIVE APPLICATION OF QUANTITATIVE STRUCTURE-ACTNITY RELATIONSHIPS 
24 
CHAPTER 1. QSAR OPTIMIZATION OF ACTIVITY, SELECTIVITY AND LACK OF DEPRESSIVITY FOR A BETA-ADRENERGIC BLOCKER. (±)-1-ISOPROPYLAMINO-3-(5-[(C2-endoBICYCLO[3.1.0]HEX-6-YL)-ETHULCARBAMOYL]-2-THIAZOLYLOXY)-PROPAN-2-OL MALEATE 26
Introduction 26
References 37
CHAPTER 2. THE USE OF QSAR IN THE SYNTHESIS OF ANTINFLAMATORY ARYLÁLIRHATIC ACIDS 
38 
INTRODUCTION 38
MATERIAL AND METHODS 
39 
RESULTS AND DISCUSSION 40
SUMMARY 44
REFERENCES 45
CHAPTER 3. BEL FREE: A NEW METHOD FOR PREDICTING BIOLOGICAL ACTIVITY USING INDICATOR VARIABLES 
48 
Introduction 48
Materials and methods 48
Prediction case studies 49
Evaluation of the prediction results 50
BEL FREE method 52
Discussion 54
Acknowledgement 54
References 54
CHAPTER 4. QUANTITATIVE STRUCTURE - ACTIVITY - STUDIES ON SOME PIPERIDINOAC ETANILIDES 
62 
Introduction 62
Material and Methods 62
Results and discussion 62
Summary 64
CHAPTER 5. STRATEGY IN DRUG RESEARCH. STRUCTURE-ACTIVITY RELATIONSHIP OF 11-SUBSTITUTED PROGESTATIONAL STEROIDS 66
Introduction 66
Continued investigations 69
Discussion 71
Literature 71
PART II: UTILIZATION OF QSAR TOOLS FOR INVESTING PHARMACON-RECEPTOR INTERACTION 
74 
CHAPTER 6. THE ROLE OF ANTONIC SITE IN THE SPECIFICITY OF CHOLINESTERASES 
76 
Introduction 76
Methods 77
Results 79
Discussion 86
Summary 89
References 90
CHAPTER 7. QSAR OF CHOLINERGIC LIGAND INTERACTIONS 94
REFERENCES 100
CHAPTER 8. QSAR OF THE INHIBITION OF CHYMOTRYPSIN BY ALKYL PHOSPHONATES 102
REFERENCES 112
CHAPTER 9. 7-SUBSTITUTED-4-HYROXYQUINOLINE-3-CARBOXYLIC ACIDS AS 
114 
INTRODUCTION 114
MATERIALS AND METHODS 115
RESULTS AND DISCUSSION 119
SUMMARY 122
ACKNOWLEDGEMENT 122
REFERENCES 122
CHAPTER 10. RECEPTOR SITE MAPPING BY MINIMAL STERIC DIFFERENCES 124
Introduction 124
Method 125
Discussion 127
References 127
Summary 127
CHAPTER 11. A SIMPLE MODEL OF DYNAMIC RECEPTOR PATTERN GENERATION 
130 
Introduction 130
Results of the Computer Simulation of the Automaton 133
Conclusions and Possible Biological Implications of the Model 136
References 137
CHAPTER 12. THEORETICAL INVESTIGATION OF THE INHIBITION OF NOREPINEPHRINE REUPTAKE BY PHENYLETHYLAMINE ANALOGUES 140
Introduction 140
Method 141
Results 144
Discussion 146
Summary 147
References 147
PART III: MATHEMATICAL AND COMPUTATIONAL TOOLS IN QSAR 148
CHAPTER 13. CHANCE FACTORS IN QSAR STUDIES 150
Method 151
Results 152
Applications to Reported Correlation Studies 155
Summary 157
Acknoavtedgements 158
Literature Cited 158
CHAPTER 14. INLERRELATIONSHIPS BETWEEN BIOLOGICAL ACTIVITIES FROM PARALLEL TESTS IN MASS SCREENING 168
Theory and Methods 168
Results and Discussion 170
Summary 174
References 174
CHAPTER 15. SAMPLE SELECTION METHODS 176
The PCMM method 176
The TMIC method 180
Summary 186
CHAPTER 16. FACTCR ANALYSIS OF CLINICAL DATA ON THE TREATMENT OF CARDIOVASCULAR DISEASES 188
Introduction 188
Method 188
Summary 193
References 193
CHAPTER 17. The Masca Model of Pharmacochemistry 194
1. Introduction 194
2. The Masca Model of Pharmacochemistry 196
3. Concluding Remarks 201
References 202
PART IV: STRUCTURE-PHARMACOKINETIC RELATIONSHIPS PHYSICOCHEMICAL AND OTHER 
204 
CHAPTER 18. QUANTITATIVE STRUCTURE-PHARMACOKINETIC RELATIONSHIPS OF SULFONAMIDES 206
Introduction 206
Results and Discussion 207
Materials and Methods 216
Summary 217
References 218
CHAPTER 19. STRUCTURE-PHARMACOKINETIC CORRELATION FOR ESTER PRODRUGS OF OXAZEPAM 220
INTRODUCTION 220
MATERIALS AND METHODS 221
RESULTS 221
DISCUSSION 224
SUMMARY 225
REFERENCES 226
CHAPTER 20. RECALCULATION OF SOME STERIMOL PARAMETERS 228
Introduction 228
Methods 228
Results and discussion 229
Summary 230
References 232
CHAPTER 21. THE CORRELATION OF BIOLOGICAL ACTIVITIES FOR ALKYL SUBSTITUTED SYSTEMS 234
References 243
CHAPTER 22. THE NON-ADDITIVITY OF p VALUES IN THE HYDROPHIL REGION 244
Introduction 244
Material and Methods 244
Results and Discussion 245
Summary 248
References 248
CHAPTER 23. EVALUATION OF STERIC FACTORS CONNECTED WITH THE HYDROPHOBIC BEHAVIOUR OF DRUG STRUCTURES 250
INTRODUCTION 250
THE CURRENT f-SYSTEM AND ITS PREDICTIVE MERITS 251
LIPOPHILIC BEHAVIOUR OF ALKYL-SUBSTITUTED BENZOIC ACIDS 253
LIPOPHILIC BEHAVIOUR OF N-ALKYLPHENOXYACETOHYDRAZIDES 256
LIPOPHILIC BEHAVIOUR OF CLONIDINES 258
ACKNOWLEDGEMENT 261
REFERENCES 262
CHAPTER 24. SOME CRITICAL REMARKS ON THE BIAGI'S METHOD FOR THE ESTIMATION OF LIPOPHILICITY OF SUBSTANCES BY MEANS OF TLC 264
References 268
CHAPTER 25. PRINCIPAL COMPONENT ANALYSIS OF PARTITION COFFICIENTS IN DIFFRENT SOLVENT SYSTEMS 270
Introduction 270
Methods 270
Results and discussion 272
Conclusions 275
Summary 276
References 276
PART V: PEPTIDES QUANTITATIVE ASPECTS OF STRUCTURE-ACTIVITY RELATIONSHIPS 278
CHAPTER 26. INVESTIGATION OF STRUCTURE-ACTIVITY RELATIONSHIPS WITH CHROMOGENIC PEPTIDYL SUBSTRATES FOR PROTEASES 280
Introduction 280
Materials and Methods 280
Results and Discussion 282
Summary 286
References 287
CHAPTER 27. A SPECIFIC QSAR MODEL FOR PEPTIDES 288
Introduction 288
Model 288
Calculation method 293
QSAR of enkephalin derivatives 293
Discussion 299
Acknowledgement 299
References 300
CHAPTER 28. EMPIRICAL ENERGY CALCULATIONS ON SOME CONFORMATIONALLY RESTRICTED ANALOGS OF ENKEPHALIN 302
INTRODUCTION 302
METHODS 303
RESULTS AND DISCUSSION 303
SUMMARY 306
REFERENCES 306
CHAPTER 29. STEREOSELECTIVITY AND AFFINITY OF OPIOID RECEPTORS FOR DIASTEREOMERIC ENKEPHALINS 308
SUMMARY 308
INTRODUCTION 309
RESULTS AND DISCUSSION 310
REFERENCES 317
CHAPTER 30. EFFECT OF THE AMINO-ACID ENVIRONMENT ON ENZYMATIC ACTION: THE SUBTILISIN CHARGE-RELAY SYSTEM 318
Acknowledgements 322
REFERENCES 322
PART VI: QSAR STUDIES OF COMPOUND SERIES 324
CHAPTER 31. QSAR IN TOXICOLOGY 326
Introduction 326
Interaction of cytochrome P-450 with xenobiotics 332
Accelerated elimination of mercury from the body through the bile 336
References 339
CHAPTER 32. SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF OXIME ETHER DERIVATIVES OF SATURATED CYCLIC KETONES 342
EXPERIMENTAL AND CALCULATIONS 342
RESULTS AND DISCUSSION 343
CONCLUSIONS 346
REFERENCES 346
CHAPTER 33. QSAR IN THE GROUP OF ERYTHROMYCIN DERIVATIVES 348
Summary 352
References 352
CHAPTER 34. QSAR STUDY ON DIFLUBENZURON ANALOGUES BY MULTIVARIATE METHODS 354
Introduction 354
Materials and Methods 355
Results and Discussion 355
Summary 360
References 361
CHAPTER 35. FREE-WILSON APPROACH TO NEW TRIMETHOPRIM CONGENERS 362
Introduction 362
Methods 362
Results and discussion 363
Summary 366
References 367
CHAPTER 36. RECEPTOR SITE MAPPING FOR CARDIOTONIC AGLYCONES BY THE MINIMAL STERIC DIFFERENCE METHOD 374
Introduction 374
Method 374
Summary 378
References 378
CHAPTER 37. QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS IN ORGANOTIN COMPOUNDS. - A COMPARISON OF DIFFERENT BIOLOGICAL TESTS 380
Introduction 380
Results 384
Conclusions 385
References 386
CHAPTER 38. QUANTITATIVE STRUCTURE-ACTIVITY ANALYSIS OF SELECTED B- ADRENOCEPTOR ANTAGONISTS 
388 
Summary 390
Reference 390
BIOLOGICAL ACTIVITY INDEX 392
COMPOUND INDEX 395
INDEX OF QSAR TERMS 398