Posts tagged Molecular docking
Pharmacophore screening, molecular docking, ADMET prediction and MD simulations for identification of ALK and MEK potential dual inhibitors
Pharmacophore screening, molecular docking, ADMET prediction and MD simulations for identification of ALK and MEK potential dual inhibitors

Anaplastic lymphoma kinase (ALK) fusion gene is a common driver gene in non-small cell lung cancer (NSCLC). The activation of mitogen-activated protein kinase (MAPK) and other related signaling pathways cause the proliferation of cancer cells. Mitogen-activated protein kinase kinase (MAPKK, also known as MEK) is a member of the ALK-MAPK signaling cascade. Recent studies have found that the drug resistance in ALK-positive NSCLC is highly dependent on the activation of the MAPK pathway, and the combined inhibition of ALK and MEK can delay or even eliminate the resistance. In this work, dual ALK/MEK inhibitors were designed through computer-aided drug design (CADD). Ten million molecules from ZINC were screened through pharmacophore models, ADMET prediction and molecular docking. Finally, 35 hit compounds were obtained. Among them, compound 1 has the highest dual inhibitory potential. The results of molecular docking, ADMET prediction and molecular dynamics (MD) simulations show that comp..... READ ARTICLE

Journal of Molecular Structure DOI:10.1016/j.molstruc.2021.131066

Authors: Haoran Zhang, Lichuan Zhang, Chenglong Gao, Rilei Yu, Congmin Kang

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Pre-Clinical, group4Kirk SmithNSCLC, ALK, Pharmacophore, Molecular docking, Molecular dynamics, ADMET prediction
Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties
Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties

Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6–33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15 showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3G1202R, with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALKL1196M and ALKG1202R mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profile..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.03.038

Authors: Hongrui Lei, Nan Jiang, Xiuqi Miao, Lingyun Xing, Ming Guo, Yang Liu, Haowen Xu, Ping Gong, Daiying Zuo, Xin Zhai

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Pre-ClinicalKirk SmithCeritinib analogs, Imidazolidin-2-one, ALK & ROS1 inhibitors, PK profiles, Molecular docking