Identification of Novel Inhibitors of Dengue Viral NS5 RNA-dependent RNA Polymerase Through Molecular Docking, Biological Activity Evaluation and Molecular Dynamics Simulations

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2025 Feb 12

PMID 39936614

Authors

Keli Zong

Chaochun Wei

Wei Li

Cong Wang

Jiajun Ruan

Xiaojing Liu

Susu Zhang

Hong Yan

Ruiyuan Cao

Xingzhou Li

Affiliations

Soon will be listed here.

Abstract

The DENV-NS5 RNA-dependent RNA polymerase (RdRp) is essential for viral replication, and one of the targets of anti-virus. In this study, the Uni-VSW module was used to virtual screen 1.6 million compounds in the ChemDiv and TargetMol (USA) database, 27 candidates were obtained. Thereby 23 candidates were selected based on their binding free energies by 50 ns MD simulations. The biological activity of the candidates and the reference compounds ( and ) were evaluated on their IC values against DENV-NGC, CC values, and selectivity index. Among these, the IC values of and were 13.06 ± 1.17 μM and 14.79 ± 7.76 μM, respectively, which were better than that of (IC =19.67 ± 1.12 μM). The comprehensive MD simulations were performed on the candidates to assess the stability behaviour and binding mechanisms. The density functional theory (DFT) analysis was also conducted to explore the structural and electronic properties.

References

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

Yokokawa F, Nilar S, Noble C, Pheng Lim S, Rao R, Tania S . Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design. J Med Chem. 2016; 59(8):3935-52. DOI: 10.1021/acs.jmedchem.6b00143. View

Pheng Lim S, Noble C, Seh C, Soh T, El Sahili A, Chan G . Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling. PLoS Pathog. 2016; 12(8):e1005737. PMC: 4976923. DOI: 10.1371/journal.ppat.1005737. View

Lu T, Chen F . Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem. 2011; 33(5):580-92. DOI: 10.1002/jcc.22885. View

Goh J, de Hayr L, Khromykh A, Slonchak A . The Flavivirus Non-Structural Protein 5 (NS5): Structure, Functions, and Targeting for Development of Vaccines and Therapeutics. Vaccines (Basel). 2024; 12(8). PMC: 11360482. DOI: 10.3390/vaccines12080865. View

Nguyen M, An S, Nguyen Y, Hyun Y, Choi H, Pham L . Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives. ACS Med Chem Lett. 2022; 13(7):1131-1136. PMC: 9290037. DOI: 10.1021/acsmedchemlett.2c00159. View

Enosi Tuipulotu D, Fumian T, Netzler N, Mackenzie J, White P . The Adenosine Analogue NITD008 has Potent Antiviral Activity against Human and Animal Caliciviruses. Viruses. 2019; 11(6). PMC: 6631109. DOI: 10.3390/v11060496. View

Koraboina C, Akshinthala P, Kumar Katari N, Adarasandi R, Babu Jonnalagadda S, Gundla R . New oxindole carboxamides as inhibitors of DENV NS5 RdRp: Design, synthesis, docking and Biochemical characterization. Heliyon. 2023; 9(11):e21510. PMC: 10665688. DOI: 10.1016/j.heliyon.2023.e21510. View

Brady O, Hay S . The Global Expansion of Dengue: How Mosquitoes Enabled the First Pandemic Arbovirus. Annu Rev Entomol. 2019; 65:191-208. DOI: 10.1146/annurev-ento-011019-024918. View

10.

Bhatnagar P, Sreekanth G, Murali-Krishna K, Chandele A, Sitaraman R . Dengue Virus Non-Structural Protein 5 as a Versatile, Multi-Functional Effector in Host-Pathogen Interactions. Front Cell Infect Microbiol. 2021; 11:574067. PMC: 8015806. DOI: 10.3389/fcimb.2021.574067. View

11.

Warren T, Wells J, Panchal R, Stuthman K, Garza N, Van Tongeren S . Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature. 2014; 508(7496):402-5. PMC: 7095208. DOI: 10.1038/nature13027. View

12.

Tully D, Griffiths C . Dengvaxia: the world's first vaccine for prevention of secondary dengue. Ther Adv Vaccines Immunother. 2021; 9:25151355211015839. PMC: 8132086. DOI: 10.1177/25151355211015839. View

13.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

14.

Pheng Lim S, Noble C, Shi P . The dengue virus NS5 protein as a target for drug discovery. Antiviral Res. 2015; 119:57-67. DOI: 10.1016/j.antiviral.2015.04.010. View

15.

Maier J, Martinez C, Kasavajhala K, Wickstrom L, Hauser K, Simmerling C . ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015; 11(8):3696-713. PMC: 4821407. DOI: 10.1021/acs.jctc.5b00255. View

16.

Bhatt S, Gething P, Brady O, Messina J, Farlow A, Moyes C . The global distribution and burden of dengue. Nature. 2013; 496(7446):504-7. PMC: 3651993. DOI: 10.1038/nature12060. View

17.

Noble C, Pheng Lim S, Arora R, Yokokawa F, Nilar S, Seh C . A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening. J Biol Chem. 2016; 291(16):8541-8. PMC: 4861426. DOI: 10.1074/jbc.M115.710731. View

18.

Yin Z, Chen Y, Schul W, Wang Q, Gu F, Duraiswamy J . An adenosine nucleoside inhibitor of dengue virus. Proc Natl Acad Sci U S A. 2009; 106(48):20435-9. PMC: 2787148. DOI: 10.1073/pnas.0907010106. View

19.

Shepard D, Undurraga E, Halasa Y, Stanaway J . The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016; 16(8):935-41. DOI: 10.1016/S1473-3099(16)00146-8. View

20.

Nascimento I, Santos-Junior P, Aquino T, Araujo-Junior J, Silva-Junior E . Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors. Eur J Med Chem. 2021; 224:113698. DOI: 10.1016/j.ejmech.2021.113698. View