       Document 0355
 DOCN  M9610355
 TI    Flexible matching of test ligands to a 3D pharmacophore using a
       molecular superposition force field: comparison of predicted and
       experimental conformations of inhibitors of three enzymes.
 DT    9601
 AU    McMartin C; Bohacek RS; Pharmaceuticals Division, CIBA-GEIGY
       Corporation, Summit, NJ; 07901, USA.
 SO    J Comput Aided Mol Des. 1995 Jun;9(3):237-50. Unique Identifier :
       AIDSLINE MED/96044959
 AB    A computer procedure TFIT, which uses a molecular superposition force
       field to flexibly match test compounds to a 3D pharmacophore, was
       evaluated to find out whether it could reliably predict the bioactive
       conformations of flexible ligands. The program superposition force field
       optimizes the overlap of those atoms of the test ligand and template
       that are of similar chemical type, by applying an attractive force
       between atoms of the test ligand and template which are close together
       and of similar type (hydrogen bonding, charge, hydrophobicity). A
       procedure involving Monte Carlo torsion perturbations, followed by
       torsional energy minimization, is used to find conformations of the test
       ligand which cominimize the internal energy of the ligand and the
       superposition energy of ligand and template. The procedure was tested by
       applying it to a series of flexible ligands for which the bioactive
       conformation was known experimentally. The 15 molecules tested were
       inhibitors of thermolysin, HIV-1 protease or endothiapepsin for which
       X-ray structures of the bioactive conformation were available. For each
       enzyme, one of the molecules served as a template and the others, after
       being conformationally randomized, were fitted. The fitted conformation
       was then compared to the known binding geometry. The matching procedure
       was successful in predicting the bioactive conformations of many of the
       structures tested. Significant deviation from experimental results was
       found only for parts of molecules where it was readily apparent that the
       template did not contain sufficient information to accurately determine
       the bioactive conformation.
 DE    Amino Acid Sequence  Aspartic Proteinases/ANTAGONISTS & INHIB
       Comparative Study  *Computers  *Drug Design  Enzyme
       Inhibitors/*CHEMISTRY  Evaluation Studies  HIV Protease
       Inhibitors/CHEMISTRY  HIV-1/ENZYMOLOGY  Ligands  Models, Molecular
       *Molecular Conformation  Molecular Sequence Data  Molecular Structure
       Monte Carlo Method  Oligopeptides/CHEMISTRY  Thermodynamics
       Thermolysin/ANTAGONISTS & INHIB  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

