Resistance mechanism of the oncogenic β3-αC deletion mutation in BRAF kinase to dabrafenib and vemurafenib revealed by molecular dynamics simulations and binding free energy calculations

Chemical Biology & Drug Design
Yuzhen NiuXiaojun Yao

Abstract

BRAF kinase is an essential target for anti-cancer drug development. Emergence of the β3-αC loop deletion mutation (ΔNVTAP) in BRAF kinase frequently occurred in human cancers seriously compromises the therapeutic efficacy of some BRAF kinase inhibitors, such as dabrafenib and vemurafenib. However, the mechanism of this resistance is still not well understood. In this study, the influence of the β3-αC deletion mutation on the binding profiles of three BRAF kinase inhibitors (AZ628, dabrafenib, and vemurafenib) with BRAFV600E or BRAFΔNVTAP was explored by conventional molecular dynamics (MD) simulations and binding free energy calculations. The simulation results indicated that the β3-αC deletion mutation enhances the flexibility of the αC helix and alters their conformations, which amplify the conformational entropy change (-TΔS) and weaken the interactions between the inhibitors and BRAF. The further per-residue binding free energy decomposition analysis revealed that the ΔNVTAP mutation changed the contributions of a few key residues to the bindings of dabrafenib or vemurafenib, such as L57, L66, W83, C84, F135, G145, and F147, but did not have obvious impact on the contributions of these residues to AZ628. Our results provid...Continue Reading

References

Feb 5, 1985·Journal of Molecular Biology·M LevittP S Stern
Dec 1, 1993·Proteins·A AmadeiH J Berendsen
Apr 26, 2001·Biophysical Chemistry·C ArcangeliS Cannistraro
Jun 18, 2002·Nature·Helen DaviesP Andrew Futreal
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Mar 4, 2008·Endocrine-related Cancer·F FrascaR Vigneri
Jun 19, 2008·Cancer Research·Clara MontagutJeffrey Settleman
Apr 10, 2009·Current Protein & Peptide Science·Saraswathi VishveshwaraPriti Hansia
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Jan 19, 2012·Antimicrobial Agents and Chemotherapy·Christoph WelschIris Antes
Dec 28, 2012·Journal of Chemical Information and Modeling·Paulette A GreenidgeRomain M Wolf
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
Nov 29, 2013·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M Beau-FallerJ Cadranel
Oct 16, 2015·Nature·Chao ZhangGideon Bollag
Jan 15, 2016·Journal of Chemical Theory and Computation·Huiyong SunTingjun Hou
Mar 22, 2016·Cancer Cell·Scott A FosterShiva Malek
May 7, 2016·Nucleic Acids Research·Broto Chakrabarty, Nita Parekh
May 21, 2016·Nucleic Acids Research·Damiano PiovesanSilvio C E Tosatto

❮ Previous
Next ❯

Citations


❮ 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.