Molecular dynamics investigation on the Asciminib resistance mechanism of I502L and V468F mutations in BCR-ABL.

08:00 EDT 21st March 2019 | BioPortfolio

Summary of "Molecular dynamics investigation on the Asciminib resistance mechanism of I502L and V468F mutations in BCR-ABL."

Asciminib, a highly selective non-ATP competitive inhibitor of BCR-ABL, has demonstrated to be a promising drug for patients with chronic myeloid leukemia. It is a pity that two resistant mutations (I502L and V468F) have been found during the clinical trial, which is a challenge for the curative effect of Asciminib. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to investigate the molecular mechanism of Asciminib resistance induced by the two mutants. The obtained results indicate that the mutations have adversely influence on the binding of Asciminib to BCR-ABL, as the nonpolar contributions decline in the two mutants. In addition, I502L mutation causes α-helix I' (αI') to shift away from the helical bundle composed of αE, αF, and αH, making the distance between αI' and Asciminib increased. For V468F mutant, the side chain of Phe468 occupies the bottom of the myristoyl pocket (MP), which drives Asciminib to shift toward the outside of MP. Our results provide the molecular insights of Asciminib resistance mechanism in BCR-ABL mutants, which may help the design of novel inhibitors.


Journal Details

This article was published in the following journal.

Name: Journal of molecular graphics & modelling
ISSN: 1873-4243
Pages: 242-249


DeepDyve research library

PubMed Articles [24134 Associated PubMed Articles listed on BioPortfolio]

A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR-ABL1 Resistance.

The constitutive BCR-ABL1 active protein fusion has been identified as the main cause of chronic myeloid leukemia. The emergence of T334I and D381N point mutations in BCR-ABL1 confer drug resistance. ...

Insecticide-resistance mechanism of Plutella xylostella (L.) associated with amino acid substitutions in acetylcholinesterase-1: A molecular docking and molecular dynamics investigation.

Acetylcholinesterase-1 (AChE1) is a vital enzyme involved in neurotransmission and represents an attractive insecticide-target for organophosphates and carbamates in Plutella xylostella (Linneaus), an...

Peeking at G-protein-coupled receptors through the molecular dynamics keyhole.

Molecular dynamics is a state of the art computational tool for the investigation of biophysics phenomenon at a molecular scale, as it enables the modeling of dynamic processes, such as conformational...

An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study.

This study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dy...

F-Box Protein-Mediated Resistance to PARP Inhibitor Therapy.

PARP inhibitor (PARPi) therapy targets BRCA1/2 mutant tumor cells, but acquired resistance limits its effectiveness. In this issue of Molecular Cell, Marzio et al. (2019) identify a novel mechanism o...

Clinical Trials [6794 Associated Clinical Trials listed on BioPortfolio]

HIV-DNA Dynamics in HIV Monoinfected or HIV/HCV Coinfected Patients

New markers of viral activity are now under investigation. Aim of the study is to investigate the efficacy of new antiretroviral drugs by monitoring HIV-DNA dynamics in HIV-positive popula...

Pharmacokinetics Study of Asciminib in Subjects With Impaired Renal Function Compared to Matched Healthy Volunteers

The purpose of this study is to characterize the pharmacokinetics (PK) and safety profile of asciminib following a single oral dose in adult subjects with renal impairment compared to a ma...

Study of Efficacy and Safety of Asciminib in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

To evaluate efficacy, safety and pharmacokinetic profile of asciminib 40mg+imatinib or asciminib 60mg+imatinib versus continued imatinib and versus nilotinib in pre-treated patients with C...

Frontline Asciminib Combination in Chronic Phase CML

Adult male and female patients with newly diagnosed Philadelphia chromosome positive (Ph+) and/or BCR-ABL1 positive CML can be included in the study until 3 months after diagnosis. A

Chemotherapy, Host Response and Molecular Dynamics in Periampullary Cancer

The CHAMP (Chemotherapy, Host response And Molecular dynamics in Periampullary cancer) study is a prospective, single-arm observational study that started Sept 1 2018. Patients diagnosed w...

Medical and Biotech [MESH] Definitions

A sequence-related subfamily of ATP-BINDING CASSETTE TRANSPORTERS that actively transport organic substrates. Although considered organic anion transporters, a subset of proteins in this family have also been shown to convey drug resistance to neutral organic drugs. Their cellular function may have clinical significance for CHEMOTHERAPY in that they transport a variety of ANTINEOPLASTIC AGENTS. Overexpression of proteins in this class by NEOPLASMS is considered a possible mechanism in the development of multidrug resistance (DRUG RESISTANCE, MULTIPLE). Although similar in function to P-GLYCOPROTEINS, the proteins in this class share little sequence homology to the p-glycoprotein family of proteins.

A computer simulation developed to study the motion of molecules over a period of time.

A class of MOLECULAR CHAPERONES whose members act in the mechanism of SIGNAL TRANSDUCTION by STEROID RECEPTORS.

A strain of Staphylococcus aureus that is non-susceptible to the action of METHICILLIN. The mechanism of resistance usually involves modification of normal or the presence of acquired PENICILLIN BINDING PROTEINS.

A type of strength-building exercise program that requires the body muscle to exert a force against some form of resistance, such as weight, stretch bands, water, or immovable objects. Resistance exercise is a combination of static and dynamic contractions involving shortening and lengthening of skeletal muscles.

Quick Search


DeepDyve research library

Relevant Topics

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...

Leukemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases. In turn, it is part of the even broader grou...

Clincial Trials
In a clinical trial or interventional study, participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or change...

Searches Linking to this Article