Iversity (GNU), 501 Jinjudaero, Jinju 52828, Korea; [email protected] (S.P.); [email protected] (G.L.) Department of Veterinary Medicine, Institute of Animal Medicine, Gyeongsang National University (GNU), Jinju 52828, Korea; [email protected] Division of Bio Medical Large Information (BK4 Plan), Investigation Institute of Life Sciences, Gyeongsang National University (GNU), Jinju 52828, Korea; [email protected] College of Cosmetics and Meals Development, Kyungnam University, Masan 631701, Korea; [email protected] Division of Life Sciences and Applied Life Science (BK21 4), Investigation Institute of Organic Science (RINS), Gyeongsang National University (GNU), 501 Jinjudaero, Jinju 52828, Korea; [email protected] Correspondence: [email protected] (M.O.K.); [email protected] (K.W.L.); Tel.: 82557721360 (K.W.L.) These authors contributed equally.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Abstract: The cyclindependent kinase 7 (CDK7) plays a crucial part in regulating the cell cycle and RNA polymerasebased transcription. Overexpression of this kinase is linked with different cancers in humans as a consequence of its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anticancer effects, driving the development of novel and much more costeffective inhibitors with enhanced selectivity for CDK7 more than other CDKs. Within the present investigation, a pharmacophorebased approach was utilized to identify prospective hit compounds against CDK7. The generated pharmacophore models had been validated and utilized as 3D queries to screen 55,578 natural druglike compounds. The obtained compounds have been then subjected to molecular docking and molecular SB 218795 GPCR/G Protein dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently employed to calculate binding affinity, revealing 4 hitsZINC20392430, SN00112175, SN00004718, and SN00262261having a much better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode evaluation displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATPbinding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity on the hits was additional checked by docking with CDK2, the close homolog structure of CDK7. On top of that, the detailed pharmacokinetic properties had been predicted, revealing that our hits have superior properties than established CDK7 inhibitors CT7001 and THZ1. Therefore, we argue that proposed hits may be crucial against CDK7related malignancies. Keywords: CDK7; cancer; pharmacophore; molecular docking; MD simulation; MMPBSA; pharmacokinetic propertiesCopyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This short article is an open access report distributed below the terms and conditions of your Propamocarb medchemexpress Inventive Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).1. Introduction Cancer is amongst the leading causes of death in the 21st century and also the most important obstruction for the upsurge of the international lifespan [1]. Consequently, the pharmaceutical industry and scientific communities have all focused on decreasing the cancerrelated deathBiomedicines 2021, 9, 1197. https://doi.org/10.3390/biomedicineshttps://www.mdpi.com/journal/biomedicinesBiomedicines 2021, 9,two ofrate, wi.
