A quantitative structure-activity relationship study on some HIV-1 protease inhibitors using molecular connectivity index

A quantitative structure-activity relationship (QSAR) study has been made o n two different series of tetrahydropyrimidinones acting as HIV-1 protease inhibitors. A structural parameter, the first order valence molecular conne ctivity index ((1)chi (v)), has been used to account for the variation in t he activity. The protease inhibition activity as well as the antiviral pote ncy of the compounds are found to be significantly correlated with (1)chi ( v) of P-2/P-2' substituents attached to the two nitrogens N1 and N3, sugges ting that substituents containing less electronegative and more saturated a toms, meaning thereby the less polar or more hydrophobic substituents, will be more advantageous. Further, if P-2 and P-2' are dissimilar, the former is found to be more effective than the latter. This difference is attribute d to a conformational change in the enzyme that may be more favorable to P- 2 binding than to P-2' binding. (C) 2001 Elsevier Science Ltd. All rights r eserved.