Dasatinib-SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations

Mingsong Shi; Lun Wang; Penghui Li; Jiang Liu; Lijuan Chen; Dingguo Xu

doi:10.1021/acsomega.1c00947

Dasatinib-SIK2 Binding Elucidated by Homology Modeling, Molecular Docking, and Dynamics Simulations

ACS Omega. 2021 Apr 15;6(16):11025-11038. doi: 10.1021/acsomega.1c00947. eCollection 2021 Apr 27.

Authors

Mingsong Shi¹, Lun Wang¹, Penghui Li², Jiang Liu¹, Lijuan Chen¹, Dingguo Xu^{2

3}

Affiliations

¹ State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
² MOE Key Laboratory of Green Chemistry and Technology, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China.
³ Research Center for Material Genome Engineering, Sichuan University, Chengdu, Sichuan 610065, China.

Abstract

Salt-inducible kinases (SIKs) are calcium/calmodulin-dependent protein kinase (CAMK)-like (CAMKL) family members implicated in insulin signal transduction, metabolic regulation, inflammatory response, and other processes. Here, we focused on SIK2, which is a target of the Food and Drug Administration (FDA)-approved pan inhibitor N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (dasatinib), and constructed four representative SIK2 structures by homology modeling. We investigated the interactions between dasatinib and SIK2 via molecular docking, molecular dynamics simulation, and binding free energy calculation and found that dasatinib showed strong binding affinity for SIK2. Binding free energy calculations suggested that the modification of various dasatinib regions may provide useful information for drug design and to guide the discovery of novel dasatinib-based SIK2 inhibitors.