Steric Fit in Quantitative Structure-Activity Relations

ISBN-13: 9783540097556 / Angielski / Miękka / 1980 / 178 str.

A.T. Balaban;A. Chiriac;I. Motoc

Opis

Although the importance of steric fit for receptor-effector 1 interactions was recognized since Emil Fischer proposed his "lock and key" theory, the whole area of steric properties is still in a very 2-4 early stage of development. We have a fairly good idea about el- tronic and hydrophobic parameters, but it is not easy to describe ste- ric shapes of molecules without a large number of data. There are se- veral cases of good QSAR's developed for rather large series of mole- 5 cules without steric parameters - for example see papers by Hansch , 6 or Franke , but the state of steric parameters is nevertheless one of the most important drawbacks, especially concerning the ability of en- compassing, within a single QSAR, molecules of different shapes and stereoisomers. From today's steric parameters, one may mention the 7 Taft parameters E ' which gave good results in organic chemistry, the S 8 10 ra th er cum b ersome way 0 f measurIng * s h ape d'ff I ere h ces 0 f Amoore - and , 11 12 AllInger ,and the L, B -B parameters of Verloop 1 4 The work described here consists of two types of approaches to the steric fit problem. The first approach consists of developing new parameters to describe different characteristics of the molecular shape (i. e. , branching, bulkiness); this is done by means of topological in- dices.

Spis treści

Detailed Contents.- 1 Introduction.- 2 Steric and other Structural Parameters for QSAR.- 2.1 Correlational Equations and Predictor Variables.- 2.2 Steric Parameters.- 2.2.1 Taft Type Steric Parameters: ES, ESc, ESo, ESe and v.- 2.2.2 Amoore Type Steric Parameters.- 2.2.3 Molecular Refractivity and Van der Waals Volume.- 2.2.4 Verloop-Hoogenstraaten-Tipker Steric Parameters.- 2.3 Indicator Variables.- 2.4 Electronic Parameters — Synopsis.- 2.5 Intermolecular Force Parameters.- 3 Topological Indices.- 3.1 Enumeration of Topological Indices.- 3.2 Applications of Topological Indices.- 4 MSD. Minimal Steric Difference (Simple Version).- 4.1 CorrelationsBiological Activity — CMSD.- 4.2 Correlations with MSD and Other Parameters.- 4.2.1 Oxytocic Activity of Oxytocine Aminoacid Replacement Derivatives.- 4.2.2 Carbamates as Acetyl Cholinesterase Inhibitors.- 4.2.3 Schrader-type Organophosphorus Compounds.- 4.2.4 Potential Cytostatic Pt(II)-Diammines.- 4.3 Comparison Between Topological Indices, MSD and Other Sterical Parameters.- 5 MTD-Receptor Site Mapping.- 5.1 Demonstration of formula C5) for ?Y(?t?).- 5.2 QSAR for ?-Chymotrypsine Catalyzed Hydrolyses of Esthers.- 5.2.1 Experimental Data. Orientation of Molecules on the Hypermolecule.- 5.2.2 Optimization Procedure. Mapping of the p2-Site.- 5.2.3 Test of the Optimized Map S*.- 5.2.4 Other QSAR on ?-Chymotrypsine Catalysis.- 5.3 Comparative MTD and Free-Wilson Study of Antiinflamatory Activity of Substituted Cortisol Derivatives.- 5.4 Comparative MTD and Free-Wilson Study of Affinity for ?-Adrenergic Receptors of Epinephrine Substitution Derivatives.- 5.5 Oestrogenic Activity.- 5.6 Dihydrofolate Reductase Inhibition.- 5.7 Other Correlational Work on MTD.- 5.8 Vertices as Indicator Variables.- 6 MCD — Monte Carlo Version for Minimal Steric Difference.- 6.1 The Method to Calculate Nonoverlapping Volumes.- 6.1.1 Description of Molecules.- 6.1.2 Calculation of MCD.- 6.1.3 Computer Implemented MCD — Calculation. The MCD — Program.- 6.1.4 Applications.- 7 Metrics in Biochemistry. The Metric Induced by Minimal Steric Differences.- 8 Conclusions.- 9 Appendix.- 9.1 The MTD/1-program.- 9.2 The MCD — program.- 9.2.1 Succession of Computation Steps in the Program.- 9.2.2 Description of the Subroutines Used.- 9.2.3 Standard Subroutines Used.- 9.2.4 Card Indexes.- 9.2.5 Input Data.- 9.2.6 Structure of Output Data.- 9.2.7 Error Messages.- 10 References.