Identification and Evaluation of Natural Compounds as Potential Inhibitors of NS2B-NS3 Zika Virus Protease: A Computational Approach

Nada Anede; Mebarka Ouassaf; Kannan R R Rengasamy; Shafi Ullah Khan; Bader Y Alhatlani

doi:10.1007/s12033-024-01357-6

Identification and Evaluation of Natural Compounds as Potential Inhibitors of NS2B-NS3 Zika Virus Protease: A Computational Approach

Mol Biotechnol. 2024 Dec 28. doi: 10.1007/s12033-024-01357-6. Online ahead of print.

Authors

Nada Anede¹, Mebarka Ouassaf¹, Kannan R R Rengasamy^{2

3}, Shafi Ullah Khan^{4

5}, Bader Y Alhatlani⁶

Affiliations

¹ Group of Computational and Medicinal Chemistry, LMCE Laboratory, University of Biskra, Biskra, Algeria.
² Laboratory of Natural Products and Medicinal Chemistry (LNPMC), Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai, 602105, India. Ragupathi.Rengasamy@nwu.ac.za.
³ Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa. Ragupathi.Rengasamy@nwu.ac.za.
⁴ Normandie Univ, Université de Caen Normandie, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for Cancer Prevention and Treatment), 14076, Caen, France.
⁵ Comprehensive Cancer Center François Baclesse, UNICANCER, 14076, Caen, France.
⁶ Unit of Scientific Research, Applied College, Qassim University, Buraydah, 52571, Saudi Arabia.

PMID: 39733219
DOI: 10.1007/s12033-024-01357-6

Abstract

The Zika virus (ZIKV), an arbovirus within the Flavivirus genus, is associated with severe neurological complications, including Guillain-Barré syndrome in affected individuals and microcephaly in infants born to infected mothers. With no approved vaccines or antiviral treatments available, there is an urgent need for effective therapeutic options. This study aimed to identify new natural compounds with inhibitory potential against the NS2B-NS3 protease (PDB ID: 5LC0), an essential enzyme in viral replication. An e-pharmacophore model was generated using a five-point (ADDRR) feature approach in the PHASE module of Schrodinger and used for the virtual screening of 26,689 natural compounds from the PubChem database. The screening yielded 14,277 prioritized compounds based on fitness scores, further refined through extra precision (XP) docking in GLIDE, resulting in 24 compounds. Eight top hits were selected following ADME analysis with SwissADME, and toxicity screening with ProTox-II identified four non-toxic lead candidates. Molecular dynamic simulations confirmed the stability of the three most promising leads, CID 44418637, CID 163078083, and CID 68734190, with binding affinities of - 7.721, - 8.226, and - 8.307 kcal/mol, respectively. MM/GBSA analysis revealed that Compounds 68734190 (- 50.192 kcal/mol) and 163078083 (- 49.947 kcal/mol) possess superior binding affinities to the ZIKV NS2B-NS3 protease compared to the reference compound (- 38.347 kcal/mol). Given their natural origin, these compounds may offer safer options to mitigate severe ZIKV-related symptoms while providing a favourable safety and pharmacokinetic profile. This study lays the groundwork for developing targeted ZIKV therapies, potentially addressing a significant unmet need in public health by reducing the incidence of ZIKV-related complications. Further experimental validation is required to confirm efficacy and address potential development challenges.

Keywords: Antiviral agents; Molecular dynamics simulation; Viral nonstructural proteins; Zika virus.