Discovery of potent Camkk1 kinase inhibitors through e-pharmacophore and molecular screening approaches

Abstract

Diabetes is recognized as a major health problem and according to WHO estimates global prevalence of diabetes is expected to increase from 171 million in 2000 to 366 million in 2030, among which 21.7% will be Indians. The chronic nature of diabetes leads to several metabolic complications like kidney failure, cardiac problems and hypertension, etc.Camkk family members are attractive and emerging targets for the development of anti-diabetic drugs. However, the selectivity of inhibitors is a crucial property as a lack of selectivity could lead to serious adverse effects. STO-609 recently reported the role of Camkks a as potent inhibitor. In this study, Combined Molecular Docking and Pharmacophore Mapping were employed to identify potent lead molecules. E-Pharmacophore based virtual screening was performed against commercially available databases to identify the best lead molecule which was docked with the targets and analyzed for the binding pattern. Also, ADME and density function theory (DFT) studies of the compound were performed and the hits that showed good binding to the active sites and that matched with the pharmacophore models were considered as possible functional molecules against Camkk1. The results from e-pharmacophore based virtual screening and MD simulations evidenced that the top three compounds namely (Lifechemicals_1, Zinc_0910993 and Binding_10131) will be a promising inhibitor for Camkk1 family.

Communicated by Ramaswamy H. Sarma

Keywords:

• Camkk1
• ADME
• E-Pharmacophore
• DFT
• diabetes

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

JJ thank the Indo-Taiwan [GITA/DST/TWIN/P-86/2019] dated: 04/03/2020, the Board of Research in Nuclear Sciences (BRNS) (35/14/02/2018 BRNS/35009), Indian Council for Medical Research (ICMR) (No.BIC/12(07)/2015), DST-Science and Engineering Research Board (SERB) (No.EMR/2016/000498), UGC Research Award (No. F. 30-32/2016(SA-II) dt 18.04.2016), DST- Fund for Improvement of S&T Infrastructure in Universities & Higher Educational Institutions (FIST) (SR/FST/LSI-667/2016) (C), DST-Promotion of University Research and Scientific Excellence (PURSE) (No. SR/PURSE Phase 2/38 (G), 2017 and MHRD-RUSA 2.0, New Delhi (F.24-51/2014-U, Policy (TNMulti-Gen), Dept. of Edn. Govt. of India, Dt. 09.10.2018), JP thanks ICMR-SRF (No: ISRM/11 (62)/2019 dated: 10/06/2019) to carry out this work.