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Insights into Saquinavir Resistance in the G48V HIV-1 Protease: Quantum Calculations and Molecular Dynamic Simulations

Kitiyaporn Wittayanarakul ^*, Ornjira Aruksakunwong ^*, Suwipa Saen-oon ^*, Wasun Chantratita , Vudhichai Parasuk ^*, Pornthep Sompornpisut ^* and Supot Hannongbua ^*

^* Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; and Virology and Molecular Microbiology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand

Correspondence: Address reprint requests to Dr. Pornthep Sompornpisut, Dept. of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Rd., Prathumwan, Bangkok 10330, Thailand. Tel.: 662-218-7604; Fax: 662-218-7598; Email: pornthep.s{at}chula.ac.th.

The spread of acquired immune deficiency syndrome has increasingly become a great concern owing largely to the failure of chemotherapies. The G48V is considered the key signature residue mutation of HIV-1 protease developing with saquinavir therapy. Molecular dynamics simulations of the wild-type and the G48V HIV-1 protease complexed with saquinavir were carried out to explore structure and interactions of the drug resistance. The molecular dynamics results combined with the quantum-based and molecular mechanics Poisson-Boltzmann surface area calculations indicated a monoprotonation took place on D25, one of the triad active site residues. The inhibitor binding of the triad residues and its interaction energy in the mutant were similar to those in the wild-type. The overall structure of both complexes is almost identical. However, the steric conflict of the substituted valine results in the conformational change of the P2 subsite and the disruption of hydrogen bonding between the –NH of the P2 subsite and the backbone –CO of the mutated residue. The magnitude of interaction energy changes was comparable to the experimental K_i data. The designing for a new drug should consider a reduction of steric repulsion on P2 to enhance the activity toward this mutant strain.