How does the novel T315L mutation of breakpoint cluster region-abelson (BCR-ABL) kinase confer resistance to ponatinib: a comparative molecular dynamics simulation study

Zhang, Hao; He, Xinheng; Ni, Duan; Mou, Linkai; Chen, Xiangyu; Lu, Shaoyong

doi:10.1080/07391102.2019.1567390

Cited by 9 publications

(2 citation statements)

References 79 publications

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“…In particular, single 100-300 ns long molecular dynamics simulation of model built mutant structures using experimentally determined wild type coordinates has been widely employed to study the effect of mutations on protein structure and dynamics and the results are reported to be in good agreement with experiment (Boopathi & Kolandaivel, 2017;Fukuyoshi et al, 2016;Narang, Shuaib, Goyal, & Goyal, 2018;Tugba & Emil, 2015). For ITPA, computational studies can supplement the existing experiments for P32T and moreover give new insight into the structure and dynamics of wildtype and other mutants (Das et al, 2019;Saldaña-Rivera, Bello, & M endez-Luna, 2019;Zhang et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Structural dynamics of inosine triphosphate pyrophosphatase (ITPA) protein and two clinically relevant mutants: molecular dynamics simulations

Houndonougbo

Pugh

VanWormer

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The inosine triphosphate pyrophosphatase (ITPA) protein is responsible for removing noncanonical purine nucleoside triphosphates from intracellular nucleotide pools. Absence of ITPA results in genomic instability and increased levels of inosine in DNA and RNA. The proline to threonine substitution at position 32 (P32T) affects roughly 15% of the global population and can modulate treatment outcomes for cancer, lupus, and hepatitis C patients. The substitution of arginine with cysteine at position 178 (R178C) is extremely uncommon and has only been reported in a small cohort of early infantile encephalopathy patients suggesting that a functional ITPA protein is required for life in humans. Here we present molecular dynamic simulations that describe the structure and dynamics of the wild-type ITPA homodimer and two of its clinically relevant mutants, P32T and R178C. The simulation results indicate that both the P32T and R178C mutations alter the structure and dynamic properties of the protein and provide a possible explanation of the experimentally observed effect of the mutations on ITPA activity. Specifically, the mutations increased the overall flexibility of the protein and changed the dominant collective motions of the top lobe as well as the helix 2 of the lower lobe. Moreover, we have identified key active-site residues that are classified as essential or intermediate for inosine triphosphate (ITP) hydrolyzing activity based on their hydrogen bond occupancy. Here we also present biochemical data indicating that the R178C mutant has very low ITP hydrolyzing activity. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

Structural dynamics of inosine triphosphate pyrophosphatase (ITPA) protein and two clinically relevant mutants: molecular dynamics simulations

Houndonougbo

Pugh

VanWormer

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…Molecular dynamics (MD) simulation analysis has proved to be a powerful and valuable tool for obtaining comprehensive information about various kinases, such as Anaplastic lymphoma kinase (ALK), breakpoint cluster region and the Ableson (BCR-Abl), and epidermal growth factor receptor (EGFR) (Bello, 2018; Kong et al, 2018; Zhang et al, 2019). Although some dynamic behaviors between Aurora A and inhibitors have been investigated by MD simulations, few studies have sought to elucidate the detailed selective mechanisms (Cheng et al, 2011; Oliveira, Ahmad & Engh, 2011; Talele & McLaughlin, 2008; Yang et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Exploration of the selective binding mechanism of protein kinase Aurora A selectivity via a comprehensive molecular modeling study

Zhang

et al. 2019

PeerJ

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BackgroundThe kinase of Aurora A has been regarded as a promising therapeutic target due to its altered expression in various human cancers. However, given the high similarity of the active binding site of Aurora A to other kinases, designing highly selective inhibitors towards Aurora A remains a challenge. Recently, two potential small-molecule inhibitors named AT9283 and Danusertib were reported to exhibit significant selectivity to Aurora A, but not to Gleevec. It was argued that protein dynamics is crucial for drug selectivity to Aurora A. However, little computational research has been conducted to shed light on the underlying mechanisms.MethodsIn this study, MM/GBSA calculations based on conventional molecular dynamics (cMD) simulations and enhanced sampling simulations including Gaussian accelerated MD (GaMD) simulations and umbrella sampling were carried out to illustrate the selectivity of inhibitors to Aurora A.ResultsThe calculation results from cMD simulation showed that the binding specificity is primarily controlled by conformational change of the kinase hinge. The protein dynamics and energetic differences were further supported by the GaMD simulations. Umbrella sampling further proved that AT9283 and Danusertib have similar potential of mean force (PMF) profiles toward Aurora A in terms of PMF depth. Compared with AT9283 and Danusertib, Gleevec has much lower PMF depth, indicating that Gleevec is more easily dissociated from Aurora A than AT9283 and Danusertib. These results not only show the selective determinants of Aurora A, but also provide valuable clues for the further development of novel potent Aurora A selective inhibitors.

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Electronic and Structural Insights of BCR-ABL Inhibitors Under LMC Treatment Perspective

Nascimento

Benicio

et al. 2022

Research Topics in Bioactivity, Environment and Energy

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How does the novel T315L mutation of breakpoint cluster region-abelson (BCR-ABL) kinase confer resistance to ponatinib: a comparative molecular dynamics simulation study

Cited by 9 publications

References 79 publications

Structural dynamics of inosine triphosphate pyrophosphatase (ITPA) protein and two clinically relevant mutants: molecular dynamics simulations

Structural dynamics of inosine triphosphate pyrophosphatase (ITPA) protein and two clinically relevant mutants: molecular dynamics simulations

Exploration of the selective binding mechanism of protein kinase Aurora A selectivity via a comprehensive molecular modeling study

Electronic and Structural Insights of BCR-ABL Inhibitors Under LMC Treatment Perspective

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