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3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results.
Drug Des Discov. 1994 Jul; 12(1):29-51.DD

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+Show Affiliations

Opera TI
Center for Molecular Design, Washington University School of Medicine, St. Louis, MO 63130, USA.
Waller CL
No affiliation info available
Marshall GR
No affiliation info available

MeSH

Binding SitesChemistry, PhysicalDrug DesignHIV Protease InhibitorsHIV-1Models, MolecularMolecular ConformationProtein BindingProtein ConformationStructure-Activity Relationship

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

7578806

Citation

Opera, T I., et al. "3D-QSAR of Human Immunodeficiency Virus (I) Protease Inhibitors. III. Interpretation of CoMFA Results." Drug Design and Discovery, vol. 12, no. 1, 1994, pp. 29-51.
Opera TI, Waller CL, Marshall GR. 3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. Drug Des Discov. 1994;12(1):29-51.
Opera, T. I., Waller, C. L., & Marshall, G. R. (1994). 3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. Drug Design and Discovery, 12(1), 29-51.
Opera TI, Waller CL, Marshall GR. 3D-QSAR of Human Immunodeficiency Virus (I) Protease Inhibitors. III. Interpretation of CoMFA Results. Drug Des Discov. 1994;12(1):29-51. PubMed PMID: 7578806.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3D-QSAR of human immunodeficiency virus (I) protease inhibitors. III. Interpretation of CoMFA results. AU - Opera,T I, AU - Waller,C L, AU - Marshall,G R, PY - 1994/7/1/pubmed PY - 1994/7/1/medline PY - 1994/7/1/entrez SP - 29 EP - 51 JF - Drug design and discovery JO - Drug Des Discov VL - 12 IS - 1 N2 - 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. SN - 1055-9612 UR - https://www.unboundmedicine.com/medline/citation/7578806/3D_QSAR_of_human_immunodeficiency_virus__I__protease_inhibitors__III__Interpretation_of_CoMFA_results_ L2 - https://antibodies.cancer.gov/detail/CPTC-PGR-2 DB - PRIME DP - Unbound Medicine ER -
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