Hydrophobicity in the design of P2/P2′ tetrahydropyrimidinone HIV protease inhibitors

Balance of hydrophobicity and volume dependent polarizability has been found to play a key role in the inhibition of HIV protease by these inhibitors. As part of an ongoing effort in understanding the role of hydrophobicity in the design of nonpeptidic HIV protease inhibitors, the QSAR study on P2/P2′ tetrahydropyrimidinone is presented in this report. Our results suggest that the balance of hydrophobicity and a volume- dependent polarizability term plays a key role in the inhibition of the viral protease by these inhibitors. The size of the substituent of ligands at particular positions that induce steric fit is crucial. The role of hydrophobicity in the design of tetrahydropyrimidinone is discussed. It has been found that a sufficient spread in the data is required to observe the optimum value of C log P for these inhibitors.