Virtual screening, molecular dynamics and density functional theory on pain inhibitors against TRPV1 associating inflammatory conditions

Jency Roshni; Mahema Sivakumar; Fuad M Alzahrani; Ibrahim F Halawani; Khalid J Alzahrani; Shankargouda Patil; Shiek S S J Ahmed

doi:10.1080/07391102.2023.2237595

Virtual screening, molecular dynamics and density functional theory on pain inhibitors against TRPV1 associating inflammatory conditions

J Biomol Struct Dyn. 2023 Jul 25:1-11. doi: 10.1080/07391102.2023.2237595. Online ahead of print.

Authors

Jency Roshni¹, Mahema Sivakumar¹, Fuad M Alzahrani², Ibrahim F Halawani², Khalid J Alzahrani², Shankargouda Patil³, Shiek S S J Ahmed¹

Affiliations

¹ Drug discovery and Multi-omics Lab, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, India.
² Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
³ College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah, USA.

PMID: 37489910
DOI: 10.1080/07391102.2023.2237595

Abstract

Transient receptor potential vanilloid 1 protein (TRPV1) is expressed widely in skin and sensory neurons that contribute to pain/heat sensation in the human system. TRPV1 gene polymorphisms are susceptible to multiple diseases and it is considered a therapeutic target for various inflammatory conditions. Among the TRPV1 variants, rs8065080 (1911 A > G) plays a vital role in painful osteoarthritis and migraine. The presence of rs8065080 polymorphism may render drug efficacy. This study aimed to identify better antagonists against wild-type and variant TRPV1 that may help in the relief of pain/inflammation. We constructed suitable TRPV1 protein structures for wild-type and rs8065080 variant through a homology modelling approach. A total of 3363 anti-inflammatory compounds with high chemical diversity and good drug-like properties were collected and screened against the generated structures. Molecular docking showed that nobilamide B had the highest binding affinity (-5.83 kcal/mol) towards the wild-type. Whereas, isoquinoline analogue displayed highest binding potency with the variant TRPV1 (-11.65 kcal/mol). Besides those, C18H15F3N4O showed affinity towards both wild-type (-5.53 kcal/mol) and variant TRPV1 (-9.75 kcal/mol). Then, molecular dynamic simulation revealed stable conformation in wild-type and variant TRPV1 upon binding of nobilmaide B, isoquinoline analogue and C18H15F3N4O. Additionally, density functional theory (DFT) using B3LYP hybrid function showed high chemical reactiveness of nobilamie B, isoquinoline analogue and C18H15F3N4O. Overall, our systematic investigations provide, C18H15F3N4O could be a potential analgesic inhibiting both wild-type and variant TRPV1 against inflammatory conditions.

Keywords: C18H15F3N4O; Transient receptor potential vanilloid 1 protein; density functional theory; dynamic simulation; isoquinoline analogue; molecular docking; nobilamide B.