Affiliations 

  • 1 Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan, 23200, Pakistan
  • 2 Pharmacology Unit, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia. subramaniyan.vetriselvan@monash.edu
  • 3 Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
  • 4 Faculty of Health and Life Sciences, INTI International University, 71800, Nilai, Malaysia
  • 5 Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box: 114, 45142, Jazan, Saudi Arabia. akahmed@jazanu.edu.sa
  • 6 Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, 21955, Makkah, Saudi Arabia
  • 7 Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, 56000, Cheras, Kuala Lumpur, Malaysia. vinoth@ukm.edu.my
  • 8 Department of Biochemistry, Abdul Wali Khan University, Mardan, Mardan, 23200, Pakistan. awadood@awkum.edu.pk
BMC Chem, 2024 Apr 18;18(1):76.
PMID: 38637900 DOI: 10.1186/s13065-024-01178-3

Abstract

Nod-like receptor protein 3 (NLRP-3), is an intracellular sensor that is involved in inflammasome activation, and the aberrant expression of NLRP3 is responsible for diabetes mellitus, its complications, and many other inflammatory diseases. NLRP3 is considered a promising drug target for novel drug design. Here, a pharmacophore model was generated from the most potent inhibitor, and its validation was performed by the Gunner-Henry scoring method. The validated pharmacophore was used to screen selected compounds databases. As a result, 646 compounds were mapped on the pharmacophore model. After applying Lipinski's rule of five, 391 hits were obtained. All the hits were docked into the binding pocket of target protein. Based on docking scores and interactions with binding site residues, six compounds were selected potential hits. To check the stability of these compounds, 100 ns molecular dynamic (MD) simulations were performed. The RMSD, RMSF, DCCM and hydrogen bond analysis showed that all the six compounds formed stable complex with NLRP3. The binding free energy with the MM-PBSA approach suggested that electrostatic force, and van der Waals interactions, played a significant role in the binding pattern of these compounds. Thus, the outcomes of the current study could provide insights into the identification of new potential NLRP3 inflammasome inhibitors against diabetes and its related disorders.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.