Computational Chemical Simulations for the Complexes of Human Proteases with HIV-1 Protease Inhibitors Using Fragment Molecular Orbital Method

Abstract

In our continuing efforts to compute biopolymers such as AIDS proteins, which are a major target for antiretroviral therapy, an all-electron quantum chemical calculation on the complexes of HIV-1 protease (HIV-1 PR) with its inhibitors has been carried out using ab initio fragment molecular orbital (FMO) method. Here, we extend this computational work with FMO method to further explore the relationship between computed binding energies and clinically reported drug effects for HIV-1 PR inhibitors, on the basis of the interaction of some human aspartyl proteases (human PRs) including renin and pepsin with HIV-1 PR inhibitors. Two inhibitor-bound renin PR complexes with Ritonavir and Saquinavir were each subjected to a FMO calculation at MP2/STO-3G level by using BioStation package. Ritonavir in the complex with the renin, which exists in human kidney, gave the largest binding energy and showed a relatively strong interaction with the renin catalytic active site residue ASP221. The present computations indicate that peptidomimetic PR inhibitors having a relatively large binding and interaction energy for human PRs as well as for HIV-1 PR can be highly effective as an AIDS agent but they can also produce unwanted side effects: renal and hepatic dysfunction and hyperglycemia (high blood sugar).