FMS-like tyrosine kinase-3 (FLT3) inhibitors with better binding affinity and ADMET properties than sorafenib and gilteritinib against acute myeloid leukemia: in silico studies
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Date
2021-09-06
Journal Title
Journal ISSN
Volume Title
Publisher
Taylor and Francis
Abstract
Over 30–35% of patients down with AML are caused by mutations of FLT3-ITD and FLT3-TKD which
keeps the protein activated while it activates other signaling proteins downstream that are involved in
cell proliferation, differentiation, and survival. As drug targets, many inhibitors are already in clinical
practice. Unfortunately, the average overall survival rate for patients on medication suffering from
AML is 5 years despite the huge efforts in this field. To perform docking simulation and ADMET studies
on selected phytochemicals against FLT3 protein receptor for drug discovery against FLT3 induced
AML, molecular docking simulation was performed using human FLT3 protein target (PDB ID: 6JQR)
and 313 phytochemicals with standard anticancer drugs (Sorafenib and Gilteritinib in addition to other
anticancer drugs). The crystal structure of the protein was downloaded from the protein data bank
and prepared using Biovia Discovery Studio. The chemical structures of the phytochemicals were
downloaded from the NCBI PubChem database and prepared using Open Babel and VConf softwares.
Molecular docking was performed using PyRx on Autodock Vina. The ADMET properties of the bestperforming compounds were calculated using SwissADME and pkCMS web servers. The results
obtained showed that glabridin, ellipticine and derivatives (elliptinium and 9-methoxyellipticine),mezerein, ursolic acid, formononetin, cycloartocarpesin, hypericin, silymarin, and indirubin are the best performing compounds better than sorafenib and gilteritinib based on their binding affinities. The top-performing compounds which had better binding and ADMET properties than sorafenib and gilteritinib could serve as scaffolds or leads for new drug discovery against FLT3 induced AM
Description
Keywords
Fms-like tyrosine kinase 3, acute myeloid leukemia, mutation, cancer of the blood;, molecular docking simulation, bioactive compounds, Bader Alshehri, University of Port Harcourt, ACE-PUTOR, ACE: Public Health and Toxicological Research
Citation
Chukwuebuka Egbuna, Kingsley C. Patrick-Iwuanyanwu, Eugene N. Onyeike, Johra Khan & Bader Alshehri (2022) FMS-like tyrosine kinase-3 (FLT3) inhibitors with better binding affinity and ADMET properties than sorafenib and gilteritinib against acute myeloid leukemia: in silico studies, Journal of Biomolecular Structure and Dynamics, 40:22, 12248-12259, DOI: 10.1080/07391102.2021.1969286