title: In-silico identification of inhibitors against mutated BCR-ABL protein of chronic myeloid leukemia: a virtual screening and molecular dynamics simulation study.
abstract: Aberrant and proliferative expression of the oncogene BCR-ABL in the bone marrow cells had been proven as the prime cause of chronic myeloid leukemia (CML). It has been established that tyrosine kinase domain of BCR-ABL protein is a potential therapeutic target for the treatment of CML. Imatinib is considered as a first-generation drug that can inhibit the enzymatic action by inhibiting the ATP binding with BCR-ABL protein. Later on, insensitivity of CML cells towards Imatinib has been observed may be due to mutation in tyrosine kinase domain of the ABL receptor. Subsequently, some other second-generation drugs have also been reported viz. Baustinib, Nilotinib, Dasatinib, Ponatinib, Bafetinib, etc., which can able to combat against mutated domain of ABL tyrosine kinase protein. By taking into account of bioavailability and resistance developed, there is an utmost need to find some more inhibitors for the mutated ABL tyrosine kinase protein. For virtual screening, a data-set has been generated by collecting the all available drug like natural compounds from ZINC and Drug Bank databases. Comparative docking analysis was also carried out on the active site of ABL tyrosine kinase receptor with reported reference inhibitors. Molecular dynamics simulation of the best screened interacting complex was done for 50 ns to validate the stability of the system. These selected inhibitors were further validated and analyzed through pharmacokinetics properties and series of ADMET parameters by in silico methods. Considering the above said parameters proposed molecules are concluded as potential leads for drug designing pipeline against CML.
authors.affiliation: a Department of Bioinformatics , Indian Institute of Information Technology Allahabad , Allahabad 211012 , Uttar Pradesh , India.
authors.forename: Himansu
authors.initials: H
authors.lastname: Kumar
authors.affiliation: a Department of Bioinformatics , Indian Institute of Information Technology Allahabad , Allahabad 211012 , Uttar Pradesh , India.
authors.forename: Utkarsh
authors.initials: U
authors.lastname: Raj
authors.affiliation: a Department of Bioinformatics , Indian Institute of Information Technology Allahabad , Allahabad 211012 , Uttar Pradesh , India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.affiliation: a Department of Bioinformatics , Indian Institute of Information Technology Allahabad , Allahabad 211012 , Uttar Pradesh , India.
authors.forename: Pritish Kumar
authors.initials: PK
authors.lastname: Varadwaj
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL protein; CML; Imatinib; tyrosine kinase