In silico identification and screening of CYP24A1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis

Abstract

Vitamin D is a key signalling molecule that plays a vital role in the regulation of calcium phosphate homeostasis and bone remodelling. The circulating biologically active form of vitamin D is regulated by the catabolic mechanism of cytochrome P450 24-hydroxylase (CYP24A1) enzyme. The over-expression of CYP24A1 negatively regulates the vitamin D level, which is the causative agent of chronic kidney disease, osteoporosis and several types of cancers. In this study, we found three potential lead molecules adverse to CYP24A1 through structure-based, atom-based pharmacophore and e-pharmacophore-based screening methods. Analysis was done by bioinformatics methods and tools like binding affinity (binding free energy), chemical reactivity (DFT studies) and molecular dynamics simulation (protein–ligand stability). Combined computational investigation showed that the compounds NCI_95001, NCI_382818 and UNPD_141613 may have inhibitory effects against the CYP24A1 protein.

Keywords:

• vitamin D
• CYP24A1
• in silico screening
• DFT analysis
• molecular dynamics

Acknowledgement

Authors acknowledge University Grants Commission-Innovative facility [Ref. No. F. 14-13/2013 (Inno/ASIST) dated: 30.03.2013], Govt of India for its support and providing the facilities for this work. John Marshal Jayaraj is grateful to DST-PURSE programme (Ref. No.Rc. SO (P&D)/DST-PURSE Phase II/10815/2017) for supporting financially as a Project Fellow. This work was supported by the Energy Efficiency & Resources Core Technology Program of the Korea Institute of Energy Technology Evaluation and Planning (KETEP), granted financial resource from the Ministry of Trade, Industry & Energy, Republic of Korea (20153030091450).