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Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA
Department of Molecular Pharmacology and Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
* Author to whom correspondence should be addressed.
Received: 30 April 2012; in revised form: 23 May 2012 / Accepted: 25 May 2012 / Published: 31 May 2012
Abstract: Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.
Keywords: multi-drug resistant HIV-1 protease; X-ray crystallography; desolvation energy
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Wang, Y.; Dewdney, T.G.; Liu, Z.; Reiter, S.J.; Brunzelle, J.S.; Kovari, I.A.; Kovari, L.C. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease. Biology 2012, 1, 81-93.
Wang Y, Dewdney TG, Liu Z, Reiter SJ, Brunzelle JS, Kovari IA, Kovari LC. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease. Biology. 2012; 1(1):81-93.
Wang, Yong; Dewdney, Tamaria G.; Liu, Zhigang; Reiter, Samuel J.; Brunzelle, Joseph S.; Kovari, Iulia A.; Kovari, Ladislau C. 2012. "Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease." Biology 1, no. 1: 81-93.