Pathological role of a point mutation (T315I) in BCR‐ABL1 protein—A computational insight

Abstract

BCR-ABL protein is one of the most potent target to treat chronic myeloid leukemia (CML). Apart from other mutations, T315I is especially challenging as it confers resistance to all first-and second-generation tyrosine kinase inhibitors. So, a thorough study of altered behavior upon mutation is crucially needed. To understand the resistance mechanism of mutant BCR-ABL protein, we organized a long-term molecular dynamics simulation (500 ns) and performed the detailed comparative conformational analysis. We found that due to mutation at 315th position (threonine to isoleucine), original structures deviated from normal, and attained a flexible conformation. Our observations pave a clear path toward designing new inhibitors against resistant BCR-ABL1 protein and suggest a strategy where additional flexibility governed by mutation could be given an appropriate consideration.

Identification of bioactive molecules from tea plant as SARS-CoV-2 main protease inhibitors

“…The produced trajectories of MD simulations were then used to generate the root mean square deviation (RMSD) and hydrogen bond graphs by various inbuilt scripts of GROMACS. MD simulations were used in several integrative studies to tackle various conditions such as cancers , identification of novel inhibitors Sadhasivam & Vetrivel, 2019;Sharma et al, 2020;Singh et al, 2019), role of various mutations (Nagarajan et al, 2020;Rajendran et al, 2018), and exploration of drug resistance mechanisms (Rajendran & Sethumadhavan, 2014).…”

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer

“…Owing to the application of a high-through sequencing method, the identification of disease-related biomarkers is effectually stated in many research articles. [14][15][16][17][18][19][20] Gene expression profiling has been used to find various differentially expressed genes (DEGs), and DNA methylome analysis has made it possible to identify differentially methylated genes (DMGs). Although multiple studies have demonstrated specific genes with aberrant DNA hypermethylation or hypomethylation in THCA, 21,22 the comprehensive profile and pathways of the interaction network remain elusive.…”

Investigation of structural stability and functionality of homodimeric gramicidin towards peptide‐based drug: a molecular simulation approach

“…25 The unfolding of proteins leads to the loss of secondary structure which reduces the stability of the molecule. 27 Therefore, secondary structures of homodimeric gramicidin peptides were interpreted using Visual Molecular Dynamics (VMD) program. 27 Therefore, secondary structures of homodimeric gramicidin peptides were interpreted using Visual Molecular Dynamics (VMD) program.…”

“…Thus, g-A exhibited high compactness in packing of atoms, which leads to enhanced its structural stability. 27,50 RMSD for g-A, g-B, and g-C were 2.75, 3.67, and 2.26 Å (Figure 2A), respectively. 49 To understand the stability of peptides, RMSF and RMSD were analyzed in which fluctuations and deviations in terms of its residue and backbone conformations play an important role.…”