COMPUTATIONAL DESIGN OF NORBORNANE-BASED HIV-1 PROTEASE INHIBITORS

A series of norbornane-based HIV-1 protease (PR) inhibitors are designed theoretically to displace the tetrahedrally coordinated internal water molecule that bridges inhibitor to flaps via hydrogen bonds. These designed inhibitors use the norbornenone oxygen atom to mimic this structural water molecule and contain diols to interact with the carboxylate oxygens of catalytic aspartates. 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 interaction energy between PR and the ligand, E-elec, the van der Waals interaction energy between PR and the ligand, E-vdW, and the difference of the solvation free energies of the complex, the receptor, and the isolated ligand, Delta G(solv). The equation obtained in previous work [Da W. Zhang, Philip Lin Huang, Sylvia Lee-Huang, John Z. H. Zhang, J Theor Comput Chem 7:485, 2008] is applied directly to calculate the binding free energy of designed norbornane-based HIV-1 PR inhibitors.