Identification of natural inhibitors of Bcr‐Abl for the treatment of chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of the hematopoietic stem cells, characterized at the molecular level by the bcr/abl gene rearrangement. Even though targeting the fusion gene product Bcr-Abl protein is a successful strategy, development of drug resistance and that of drug intolerance are currently the limitations for Bcr-Abl-targeted CML therapy. With an aim to develop natural Bcr-Abl inhibitors, we performed virtual screening (VS) of ZINC natural compound database by docking with Abl kinase using Glide software. Two natural inhibitors ZINC08764498 (hit1) and ZINC12891610 (hit2) were selected by considering their high Glide docking score and critical interaction with the hinge region residue Met-318 of Abl kinase. The reactivity of the two molecules was assessed computationally by density functional theory calculations. Further, the conformational transition, hydrogen bond interactions, and the binding energies were investigated during 10-ns molecular dynamics simulation of the Abl-hit complex. When tested in vitro, hit1 compared to hit2 showed selective inhibition of cell proliferation and induction of apoptosis in Bcr-Abl-positive K-562 leukemia cells. In summary, our results demonstrate that ZINC08764498, a coumarin derivative identified through VS, is a potential natural inhibitor for the treatment of CML.

Brassinin Induces Apoptosis, Autophagy, and Paraptosis via MAPK Signaling Pathway Activation in Chronic Myelogenous Leukemia Cells

“…Chronic myelogenous leukemia (CML) is a major hematopoietic disorder marked by the presence of the Philadelphia chromosome (Ph), which is generated when chromosomes 9 and 22 break and exchange their parts [1,2]. This alteration can result in the aberrant activation of Bcr-abl kinase [3,4], which in turn can regulate the aberrant tumorigenesis through stimulating the initiation of diverse signal transduction pathways, including a mitogen-activated protein kinase (MAPK), and a Janus kinase/signal transducer and activator of transcription (JAK/STAT), and the phosphatidylinositol 3 kinase (PI3K) signaling pathway, and the nuclear factor-κB (NF-κB) [5][6][7][8][9]. Imatinib mesylate is the primary tyrosine kinase that has been used to target Bcr-abl and has been clinically approved for the management of CML [10,11].…”

Molecular modeling piloted analysis for semicarbazone derivative of curcumin as a potent Abl-kinase inhibitor targeting colon cancer

“…1). Both the compounds have indicated the formation of an H bond with MET 318 with the hydroxyl group of the curcumin and derivative scaffold which has been previously observed as a key interaction (Parcha et al 2017). The additional hydrogen-bond interaction formed by the curcuminsemicarbazide complex was ILE 313 which has been previously reported to be favorable interaction for the complex (Zhou et al 2016).…”

In silico Evaluation of the Antileukemia Activities of Thymoquinone by Targeting FLT3-ITD and BCR-ABL Signaling in Myeloid leukemia

“…The interaction of TQ with the active site of BCR-ABL revealedless affinity and higher free binding energy than imatinib.The results agree with previous findings that revealed that two ZINC natural compounds, ZINC08764498 and ZINC12891610, have potential binding affinities toward BCR-ABL oncoprotein. 31 The docked conformation of PI3K, Akt, and mTOR proteins clearly showed numerous potential interactions with TQ's active conformation (Figures 3, 4, and 5). The chemical interaction between TQ and PI3K showed a pi sigma bond with ILE933, a Pi sulfur bond to CYS883, a pi lone pair to THR886, and five alkyl bonds to VAL930, ARG894, HIS909, ILE899, and PHE938 with a free binding energy of -7.02 Kcal/mol (Figure 3A).…”