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Imidazole1,5-apyridine derivatives as EGFR tyrosine kinase inhibitors unraveled by umbrella sampling and steered molecular dynamics simulations
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Imidazole1,5-apyridine derivatives as EGFR tyrosine kinase inhibitors unraveled by umbrella sampling and steered molecular dynamics simulations
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Journal Article
Imidazole1,5-apyridine derivatives as EGFR tyrosine kinase inhibitors unraveled by umbrella sampling and steered molecular dynamics simulations
2024
Overview
Although the use of the tyrosine kinase inhibitors (TKIs) has been proved that it can save live in a cancer treatment, the currently used drugs bring in many undesirable side-effects. Therefore, the search for new drugs and an evaluation of their efficiency are intensively carried out. Recently, a series of eighteen imidazole[1,5-a]pyridine derivatives were synthetized by us, and preliminary analyses pointed out their potential to be an important platform for pharmaceutical development owing to their promising actions as anticancer agents and enzyme (kinase, HIV-protease,…) inhibitors. In the present theoretical study, we further analyzed their efficiency in using a realistic scenario of computational drug design. Our protocol has been developed to not only observe the atomistic interaction between the EGFR protein and our 18 novel compounds using both umbrella sampling and steered molecular dynamics simulations, but also determine their absolute binding free energies. Calculated properties of the 18 novel compounds were in detail compared with those of two known drugs, erlotinib and osimertinib, currently used in cancer treatment. Inspiringly the simulation results promote three imidazole[1,5-a]pyridine derivatives as promising inhibitors into a further step of clinical trials.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/57
/ 631/67
/ 639/638
/ Absolute protein binding free energy
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Epidermal growth factor receptor (EGFR)
/ Epidermal growth factor receptors
/ ErbB Receptors - antagonists & inhibitors
/ Erlotinib Hydrochloride - chemistry
/ Erlotinib Hydrochloride - pharmacology
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Molecular Docking Simulation
/ Molecular Dynamics Simulation
/ Protein Kinase Inhibitors - chemistry
/ Protein Kinase Inhibitors - pharmacology
/ Sampling
/ Science
/ Steered molecular dynamics simulation
