How Mutations Can Resist Drug Binding yet Keep HIV-1 Protease Functional

Biochemistry
Rajeswari Appadurai, Sanjib Senapati

Abstract

Human immunodeficiency virus-1 (HIV-1) protease is an important drug target for acquired immune deficiency syndrome therapy. Nearly 10 small molecule drugs have been approved by the Food and Drug Administration (FDA). However, prolonged use of these drugs produced protease mutants that are not susceptible to many of these drugs. The mutated proteases, however, continue to cleave the substrate peptides and thus remain largely functional. This poses a major challenge for the treatment strategies. Thus, it has become imperative to understand how these mutations induce drug resistance while maintaining the enzymatic activity of this protein. Here, we perform a comprehensive study of the wild type (WT) and clinically relevant mutated protease bound to a series of FDA-approved drugs and substrates of varying sequences to unravel the mechanism of unhindered activity of the drug-resistant protease variants. Our results from large molecular dynamics simulations suggest that while binding of the substrate to WT and protease mutants involves multiple H-bonding interactions between substrate subsites and the protease's main chain atoms, the drug binds primarily through the hydrophobic interactions with the side chains of protease's active ...Continue Reading

References

Sep 1, 1992·Biochemistry·E S FurfineD J Porter
Feb 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·H G KräusslichC A Carter
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Dec 13, 1996·The Journal of Biological Chemistry·Z Szeltner, L Polgár
Dec 16, 1997·Journal of Medicinal Chemistry·S W KaldorJ H Tatlock
Jul 29, 2000·Bioorganic & Medicinal Chemistry Letters·T A RanoJ R Tata
Jul 19, 2002·Biophysical Journal·Joanna TrylskaPaweł Grochowski
Jan 10, 2003·Nucleic Acids Research·Soo-Yon RheeRobert W Shafer
Jun 26, 2003·Protein Science : a Publication of the Protein Society·Etsuko KatohRieko Ishima
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Feb 23, 2007·Chemical Biology & Drug Design·Chia-En A ChangJ Andrew McCammon
Jul 24, 2007·Acta Crystallographica. Section D, Biological Crystallography·Holly HeasletC David Stout
Sep 11, 2008·Journal of Computer-aided Molecular Design·Jacob Kongsted, Ulf Ryde
Jan 15, 2009·Journal of the American Chemical Society·Luis GalianoGail E Fanucci
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Jul 28, 2010·Antimicrobial Agents and Chemotherapy·Soo-Yon RheeRobert W Shafer
Mar 12, 2011·The Protein Journal·Zhigang LiuLadislau C Kovari
May 18, 2011·Proceedings of the National Academy of Sciences of the United States of America·John M LouisJane M Sayer
Jun 4, 2011·Acta Crystallographica. Section D, Biological Crystallography·Ravikiran S YedidiLadislau C Kovari
Dec 25, 2012·Journal of Chemical Theory and Computation·T SteinbrecherD A Case
Sep 16, 2014·Biochimica Et Biophysica Acta·Rodrigo Galindo-MurilloThomas E Cheatham
Jul 9, 2013·Journal of Chemical Theory and Computation·Daniel R Roe, Thomas E Cheatham

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Citations

Jan 9, 2021·Journal of Molecular Graphics & Modelling·Suchetana GuptaSanjib Senapati
Aug 31, 2019·The Journal of Physical Chemistry. B·Mohd Ahsan, Sanjib Senapati
Oct 20, 2018·Chemical Reviews·Vern L Schramm

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