DoMCoSAR: A novel approach for establishing the docking mode that is consistent with the structure-activity relationship. Application to HIV-1 protease inhibitors and VEGF receptor tyrosine kinase inhibitors

DoMCoSAR is a novel. approach for statistically determining the docking mod e that is consistent with a structure-activity relationship. The approach e stablishes the binding mode for the compounds in a chemical series with the assumption that all molecules exhibit the same binding mode. It involves t hree stages. In the first stage all molecules that belong to a given chemic al series are docked to the active site of the protein target. The only bia s used in the docking at this stage involves the location of the protein bi nding site. Coordinates of the common substructure (CS) that results from t he unbiased docking are then clustered to establish the major substructure docking modes. In the second stage all molecules are docked to the major do cking modes (MDMs) with constraints based on the common substructure. The t hird stage generates, for the major docking modes, interaction-based descri ptors that include electrostatic, VDW, strain, and solvation contributions. The problem of docking mode evaluation is now reduced to the question of w hich descriptor set is more predictive. To establish a quantitative compari son of the descriptor sets associated with the major docking modes, we use 50 instances of random 4-fold cross-validation. For each 4-fold cross-valid ation the predictive squared correlation coefficient (R-2) is computed. t-T ests are applied to establish significance of the differences in mean R-2 f or one docking mode versus another. We test the methodology on two test cas es: HIV-1 protease inhibitors (Holloway et al. J. MEd. Chem. 1995, 38, 305- 317) and vascular endothelial growth factor (VEGF) receptor tyrosine kinase oxoindoles (Sun ct al. J. Med. Chem. 1998, 41, 2588-2603). For both test c ases there is statistically significant preference for the binding mode con sistent with the X-ray structure. The appeal of this methodology is that re searchers gain the objectivity of statistical justification for the selecte d docking mode. The methodology is relatively insensitive to subtle variati ons of the protein structure that include, but are not limited to, side cha in and small backbone rearrangement during binding. In addition, predictive models that result from the approach can be used to further optimize chemi cal series.