c © World Scientific Publishing Company DESIGN OF HYBRID INHIBITORS TO HIV-1 PROTEASE

protease (PR) inhibitors are designed to increase the binding affin-ity with PR subsites based on the quantum analysis of the contributions of molec-ular fragments in six FDA-approved PR drugs to the total binding interaction. The binding free energies were estimated by modified linear interaction energy approach [Zoete H, Michielin O, Karplus M, J Comput Aided Mol Des 17:861, 2003], in which the binding free energy is written as a linear combination of the electrostatic interac-tion energy between PR and the ligand, Eelec, the van der Waals interaction energy between PR and the ligand, EvdW, and the difference of the solvation free energies of the complex, the receptor and the isolated ligand, ∆Gsolv. The parameters of these energy terms were fitted for a training set of 14 HIV-1 protease–inhibitor complexes of known 3D structure with a correlation coefficient of 0.91 and an unsigned mean error of 0.83 kcal/mol. 1