Structural Elucidation of Rift Valley Fever Virus L Protein towards the Discovery of Its Potential Inhibitors

Mubarak A Alamri; Muhammad Usman Mirza; Muhammad Muzammal Adeel; Usman Ali Ashfaq; Muhammad Tahir Ul Qamar; Farah Shahid; Sajjad Ahmad; Eid A Alatawi; Ghadah M Albalawi; Khaled S Allemailem; Ahmad Almatroudi

doi:10.3390/ph15060659

Structural Elucidation of Rift Valley Fever Virus L Protein towards the Discovery of Its Potential Inhibitors

Pharmaceuticals (Basel). 2022 May 25;15(6):659. doi: 10.3390/ph15060659.

Authors

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 16273, Saudi Arabia.
² Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada.
³ 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan 430070, China.
⁴ Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan.
⁵ Department of Health and Biological Sciences, Abasyn University, Peshawar 25000, Pakistan.
⁶ Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁷ Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.
⁸ Department of Laboratory and Blood Bank, King Fahd Specialist Hospital, Tabuk 47717, Saudi Arabia.

Abstract

Rift valley fever virus (RVFV) is the causative agent of a viral zoonosis that causes a significant clinical burden in domestic and wild ruminants. Major outbreaks of the virus occur in livestock, and contaminated animal products or arthropod vectors can transmit the virus to humans. The viral RNA-dependent RNA polymerase (RdRp; L protein) of the RVFV is responsible for viral replication and is thus an appealing drug target because no effective and specific vaccine against this virus is available. The current study reported the structural elucidation of the RVFV-L protein by in-depth homology modeling since no crystal structure is available yet. The inhibitory binding modes of known potent L protein inhibitors were analyzed. Based on the results, further molecular docking-based virtual screening of Selleckchem Nucleoside Analogue Library (156 compounds) was performed to find potential new inhibitors against the RVFV L protein. ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicity analysis of these compounds was also performed. Besides, the binding mechanism and stability of identified compounds were confirmed by a 50 ns molecular dynamic (MD) simulation followed by MM/PBSA binding free energy calculations. Homology modeling determined a stable multi-domain structure of L protein. An analysis of known L protein inhibitors, including Monensin, Mycophenolic acid, and Ribavirin, provide insights into the binding mechanism and reveals key residues of the L protein binding pocket. The screening results revealed that the top three compounds, A-317491, Khasianine, and VER155008, exhibited a high affinity at the L protein binding pocket. ADME analysis revealed good pharmacodynamics and pharmacokinetic profiles of these compounds. Furthermore, MD simulation and binding free energy analysis endorsed the binding stability of potential compounds with L protein. In a nutshell, the present study determined potential compounds that may aid in the rational design of novel inhibitors of the RVFV L protein as anti-RVFV drugs.

Keywords: MD simulation; RVFV; RdRp; docking; structural modeling; virtual screening.

Grants and funding

This research received no external funding.