Document Detail

Three-dimensional quantitative structure-activity relationship of angiotesin-converting enzyme and thermolysin inhibitors. II. A comparison of CoMFA models incorporating molecular orbital fields and desolvation free energies based on active-analog and complementary-receptor-field alignment rules.
MedLine Citation:
PMID:  8360884     Owner:  NLM     Status:  MEDLINE    
The utility of comparative molecular field analysis (CoMFA), a three-dimensional Quantitative Structure-Activity Relationship (3-D QSAR) paradigm, as a tool to aid in the development of predictive models has been previously addressed (Depriest, S.D. et al., J. Am. Chem. Soc. 1993, in press). Although predictive correlations were obtained for angiotensin-converting and thermolysin inhibitors, certain inadequacies of the CoMFA technique were noted. Primarily, CoMFA steric and electrostatic fields alone do not fully characterize the zinc-ligand interaction. Previously, this was partially rectified by the inclusion of indicator variables into the QSAR table to designate the class of zinc-binding ligand. Recent advances in molecular modeling technology have allowed us to further address this limitation of the preceding study. Using molecular orbital fields derived from semiempirical calculations as additional descriptors in the QSAR table, predictive correlations were produced based on CoMFA and molecular orbital fields alone--indicator variables no longer being necessary. Arbitrary information concerning the alignment of molecules under study within the active-site introduces ambiguities into the CoMFA study. Crystallographic information detailing the binding mode of several thermolysin enzyme inhibitors has previously been used as a guide for the alignment of additional, noncrystallized, inhibitors. However, this process was complicated by the lack of parameters for zinc in the molecular mechanical force field. Therefore, zinc-ligand interactions were ignored during the standard minimization procedure. The use of field-fit minimization using complementary receptor fields as templates is presented as a possible solution to the problem. Predictive correlations were obtained from analyses based on this method of molecular alignment. The availability of crystallographic data for thermolysin enzyme-inhibitor complexes allowed for an alternate definition of the CoMFA region. Herein, promising results from analyses using actual receptor active-site atom probe atoms are presented.
C L Waller; G R Marshall
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  36     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1993 Aug 
Date Detail:
Created Date:  1993-09-24     Completed Date:  1993-09-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2390-403     Citation Subset:  IM    
Center for Molecular Design, Washington University, St. Louis, Missouri 63130-4899.
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MeSH Terms
Angiotensin-Converting Enzyme Inhibitors / chemistry,  pharmacology*
Models, Molecular*
Molecular Structure
Structure-Activity Relationship
Thermolysin / antagonists & inhibitors*,  chemistry
Grant Support
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; EC

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