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

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.