title: 3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results.
abstract: 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.
authors.affiliation: Center for Molecular Design, Washington University School of Medicine, St. Louis, MO 63130, USA.
authors.forename: T I
authors.initials: TI
authors.lastname: Opera
authors.forename: C L
authors.initials: CL
authors.lastname: Waller
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D001665:Binding Sites; D002627:Chemistry, Physical / Q000379:methods; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors