       Document 0954
 DOCN  M9620954
 TI    3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III.
       Interpretation of CoMFA results.
 DT    9602
 AU    Opera TI; Waller CL; Marshall GR; Center for Molecular Design,
       Washington University School of; Medicine, St. Louis, MO 63130, USA.
 SO    Drug Des Discov. 1994 Jul;12(1):29-51. Unique Identifier : AIDSLINE
       MED/96062924
 AB    Comparative Molecular Field Analysis (CoMFA), a three-dimensional
       quantitative structure-activity relationship (3D-QSAR) paradigm (Cramer,
       R.D.; et al. (1988), J. Am. Chem. Soc., 110, 5959-5967), correlates
       variations in the (experimental) biological activity with 3D variance in
       the steric and electrostatic field of modeled compounds. Of general
       interest to the drug design area is the interpretation of CoMFA results,
       in order to gain maximum benefit from an established 3D-QSAR model.
       CoMFA studies report results using the standard deviation (stdev)
       times(*) coefficient (beta) field and its contributions to make SAR
       statements. This field is the scalar product of the absolute stdev of
       the CoMFA field at a lattice point and the QSAR equation coefficient
       (beta) at the same point. Negative beta values yield detrimental
       contributions, while positive beta values are considered beneficial. The
       QSAR equation is based on actual field values, therefore both positive
       and negative field values can have beneficial effect to the target
       property (Y), depending on the sign of beta. The results of a CoMFA
       model on 59 HIV-1 protease (HIV-PR) inhibitors (Waller, C.L.; et al.
       (1993), J. Med. Chem., 36, 4152-4160) were compared with the HIV-PR
       crystal structure to analyze the correspondence between CoMFA fields and
       ligand binding regions in the enzyme. Local steric and electrostatic
       interactions were analyzed in terms of various field values and beta
       coefficients. While redundant for some regions, other field contours
       besides stdev* beta bring additional information. Using this method, we
       observed a unique region with negative beta values for the electrostatic
       field (based on a -1 charged probe) located opposite of the scissile
       bond, between P1 and P1', where steric stdev* beta values are positive.
       Four hydrophobic residues in the HIV-PR crystal delimit the region,
       which is suggested as a new potential hydrophobic binding site for the
       inhibitors. The same region was confirmed using the stdev* beta contours
       of a HINT (Kellogg, G.; et al. (1991), J. Comput.-Aided Mol. Design, 5,
       545-552) calculation on the same model. The steric, electrostatic and
       lipophilic fields of the CoMFA and HINT models are presented in various
       forms, and the information extracted is detailed.
 DE    Binding Sites  Chemistry, Physical/METHODS  Comparative Study  Drug
       Design  HIV Protease Inhibitors/*CHEMISTRY/*METABOLISM/PHARMACOLOGY
       HIV-1/*ENZYMOLOGY  Models, Molecular  Molecular Conformation  Protein
       Binding  Protein Conformation  Structure-Activity Relationship  JOURNAL
       ARTICLE

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

