Theoretical calculation and prediction of P-glycoprotein-interacting drugsusing MolSurf parametrization and PLS statistics

A method for the modelling and prediction of P-glycoprotein-associated ATPa se activity using theoretically computed molecular descriptors and multivar iate statistics has been investigated using 22 diverse drug-like compounds. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, pola rizability and hydrogen bonding. The multivariate partial least squares pro jections to latent structures (PLS) method was used to delineate the relati onship between the P-glycoprotein-associated ATPase activity and the theore tically computed molecular descriptors. The PLS analysis of the entire data set, with the exclusion of tamoxifen, resulted in one significant PLS comp onent according to cross-validation with R-2=0.718, Q(2)=0.695, S.D. =0.475 , F=48.37, RMSEtr=0.452, p<0.001. Properties associated with the size of th e molecular surface, polarizability and hydrogen bonding had the largest im pact on the P-glycoprotein-associated ATPase activity. All these properties should be high to promote high ATPase activity. (C) 2000 Elsevier Science B.V. All rights reserved.