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Synthesis, Molecular Docking, Molecular Dynamics Studies and Biological Evaluation of 4H-Chromone-1,2,3,4-tetrahydropyrimidine-5carboxylate Derivatives as Potential Anti-Leukemic Agents Zahra Dolatkhah, Shahrzad Javanshir, Ahmad Shahir Sadr, jaber hosseini, and Soroush Sardari J. Chem. Inf. Model., Just Accepted Manuscript • Publication Date (Web): 19 May 2017 Downloaded from http://pubs.acs.org on May 20, 2017
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Journal of Chemical Information and Modeling is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of Chemical Information and Modeling
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Synthesis, Molecular Docking, Molecular Dynamics
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Studies and Biological Evaluation of 4H-Chromone-
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1,2,3,4-tetrahydropyrimidine-5-carboxylate
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Derivatives as Potential Anti-Leukemic Agents
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Zahra Dolatkhah a, Shahrzad Javanshir*a, Ahmad Shahir Sadr*b,c, Jaber Hosseinia, Soroush
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Sardari d a
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Heterocyclic chemistry Research Laboratory, Department of Chemistry, Iran University of
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Science and Technology, Tehran 16846-13114, Iran. b
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9613873136, Iran. c
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Bioinformatics Research Center, Sabzevar University of Medical Sciences, Sabzevar
Bioinformatics Research Center, Cheragh Medical institute & Hospital, Kabul 1001-1007, Afghanistan.
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Drug Design and Bioinformatics Unit, Department of Medical Biotechnology, Biotechnology
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Research Center, Pasteur Institute of Iran, Pasteur Avenue, Tehran 13164, Iran
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Keywords; Molecular Docking, Molecular Dynamic, Anti-Leukemic Agents, Targeted therapy
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Nano-catalyst, 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylate
ACS Paragon Plus Environment
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Journal of Chemical Information and Modeling
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ABSTRACT
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Series
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synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl
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acetoacetate and urea or thiourea, using MCM-41-SO3H as an efficient Nano-catalysts, and
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evaluated for their anti-cancer activity using a combined in silico docking and molecular
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dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl
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oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the
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target protein with synthesized compounds and ATP. AutoDock runs resulted in binding energy
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scores from -7.8 to -10.16 kcal/mol for AutoDock 4 and -6.9 to -8.5 (Kcal/mol) for AutoDock
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Vina. Furthermore, molecular dynamics (MD) simulations are performed using Gromacs for up
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to 20 ns simulation time investigating the stability of ligand-protein complex. Finally, a
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theoretical experiment using MD simulation for 10 ns was performed without defining the initial
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coordinates and the affinity binding of ligand to receptors was directly studied, which revealed
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that the ligand approaches the active sites. The relative free binding energy, for the structure 06
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(S06) which has the highest binding energy in Autodock 4 and Vina (-10.10 and -8.5 Kcal/mol
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respectively), was also evaluated by the molecular mechanics [MM] with Poisson–Boltzmann
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[PB] and surface area solvation (MM-PBSA) method using g_mmpbsa tools for the last 15 ns
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MD. Based on binding energy scores, a negative binding energy value of 73.6 Kcal/mol, S06
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was recognized as the dominant potential inhibitors. The cytotoxic properties of S06 was
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evaluated against three cell lines, acute T cell leukemia (Jurkat), human chronic myelogenous
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leukemia (K562) and human fore skin fibroblast (Hu02) using the microculture tetrazolium test
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MTT assay. Cisplatin was used as reference agent. The results indicated that S06 has higher
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Safety Index (SI=0.73, IC50 = 152.64 µg/ml for Jurkat and IC50 = 110.25 μg/ml for Hu02, P
