药效团
虚拟筛选
MAPK/ERK通路
分子动力学
氢键
对接(动物)
化学
激酶
计算生物学
生物物理学
组合化学
生物化学
立体化学
分子
计算化学
生物
有机化学
医学
护理部
作者
Yafeng Tian,Mi Zhang,Panpan Heng,Hua Hou,Baoshan Wang
标识
DOI:10.1080/07391102.2023.2204495
摘要
As the downstream component of the mitogen-activated protein kinases (MAPK) pathway, the extracellular signal-regulated kinase (ERK) is responsible for phosphorylating a broad range of substrates in cell proliferation, differentiation, and survival. Direct targeting the ERK proteins by the piperidinopyrimidine urea-based inhibitors has been demonstrated to be an effective way to block the MAPK signaling pathway in inhibiting tumor growth. In order to discover better inhibitors, a computer-aided drug design (CADD) approach was employed to reveal the pharmacological characteristics and mechanisms of action. The pharmacophore model was generated on the basis of the compounds with eight features, i.e., four hydrogen bond acceptor atoms, one hydrogen bond donor atom, and three hydrophobic centers. A total of 14 hit compounds were obtained through virtual screening. Two potential inhibitors, namely VS01 and VS02, have been identified by molecular docking and molecular dynamics simulations. Both compounds are capable of attaching to the ERK pocket precisely. The binding free energies of VS01 and VS02 are about 15 kJ/mol and 4 kJ/mol stronger than that of the clinic Ulixertinib because of the characteristic hydrogen bonding, electrostatic, and hydrophilic interactions. The present theoretical investigations shed new light on the rational design of the potential ERK inhibitors to stimulate further experimental tests.Communicated by Ramaswamy H. Sarma.
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