Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease.
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.
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. yowang@med.wayne.edu.
Yong
Y
Wang
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. tdewdne@med.wayne.edu.
Tamaria G
TG
Dewdney
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. zgliu0805@yahoo.com.
Zhigang
Z
Liu
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. sreiter@med.wayne.edu.
Samuel J
SJ
Reiter
Department of Molecular Pharmacology and Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. j-brunzelle@northwestern.edu.
Joseph S
JS
Brunzelle
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. ikovari@med.wayne.edu.
Iulia A
IA
Kovari
Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA. kovari@med.wayne.edu.
Ladislau C
LC
Kovari