Energetics of mutation-induced changes in potency of lersivirine against HIV-1 reverse transcriptase

The Journal of Physical Chemistry. B
Parimal Kar, Volker Knecht

Abstract

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy for the treatment of HIV-1. A common problem with the first generation NNRTIs is the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular, K103N and Y181C, which lead to resistance to the entire class of inhibitor. Here we have evaluated the relative affinity of the newly designed NNRTI lersivirine (LRV) against drug-resistant mutations in HIV-1 RT using the molecular mechanics generalized Born surface area (MM-GBSA) method. Eight single and one double mutant variants of RT are considered. Our results are in good agreement with experimental results and yield insights into the mechanisms underlying mutation-induced changes in the potency of LRV against RT. The strongest (54-fold) increase in the dissociation constant is found for the mutant F227C, originating from reduced electrostatic and van der Waals interactions between LRV and RT as well as a higher energetic penalty from the desolvation of polar groups. For the mutants K103N and Y181C only a moderate (2-fold) increase in the dissociation constant is found, due to a balance of opposite changes in the polar solvation as well as the elect...Continue Reading

References

Jan 1, 1992·Annual Review of Cell Biology·J M Whitcomb, S H Hughes
Dec 29, 1989·Biochemical and Biophysical Research Communications·M BabaT Miyasaka
Apr 1, 1995·Nature Structural Biology·R EsnoufD Stuart
Jan 1, 1996·Advances in Experimental Medicine and Biology·W W Freimuth
Jan 7, 2000·Journal of Molecular Biology·C M Reyes, P A Kollman
May 29, 2002·HIV Clinical Trials·Vincent Soriano, Carmen de Mendoza
Oct 24, 2002·Journal of Computational Chemistry·Araz JakalianChristopher I Bayly
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Feb 7, 2006·Journal of Molecular Graphics & Modelling·Junmei WangDavid A Case
May 10, 2008·Science·Bruce D Walker, Dennis R Burton
May 7, 2009·FEBS Letters·Parimal KarSiegfried Höfinger
Nov 9, 2010·Proteomics·Remigiusz WorchThomas Weidemann
May 21, 2011·The Journal of Physical Chemistry. B·Parimal KarVolker Knecht
Feb 22, 2012·Journal of Computer-aided Molecular Design·Parimal Kar, Volker Knecht
May 5, 2012·The Journal of Physical Chemistry. B·Parimal Kar, Volker Knecht

❮ Previous
Next ❯

Citations

Oct 17, 2013·Expert Opinion on Investigational Drugs·Martin Platten, Gerd Fätkenheuer
Jan 20, 2021·Journal of Biomolecular Structure & Dynamics·Uma ShankarAmit Kumar
Jul 28, 2021·Chemometrics and Intelligent Laboratory Systems : an International Journal Sponsored by the Chemometrics Society·Vijay H MasandMagdi E A Zaki

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

© 2021 Meta ULC. All rights reserved