September 27, 2025

Structure‐Based In Silico Discovery of Thymidine Kinase Inhibitors Targeting the Fatal Goatpox Virus: Integrating Multi‐Library Screening and Molecular Dynamic Simulation

Key Points

The study identifies thymidine kinase inhibitors with high binding affinities for goatpox virus.
Among screened compounds, dolutegravir and indirubin-5-sulphonate displayed the best binding affinities at -9.9 and -10.5 kcal/mol.
Molecular dynamics simulations confirmed the stability of the selected ligand-thymidine kinase complexes.
This research presents a comprehensive framework for developing new antiviral therapies against capripox viruses.

Abstract

Abstract Goat‐Pox Virus (GTPV), a highly virulent Capri‐pox virus (CaPV) poses significant economic threats due to high morbidity and mortality in livestock. While vaccination remains the primary control strategy, frequent outbreaks highlight the urgent need for targeted antiviral therapies. The Thymidine Kinase protein sequence was retrieved from the NCBI database, and its 3D structure was predicted using the Robetta server, refined with GalaxyRefine, and validated via SAVES v6.0, ERRAT (90.06%), and ProSa ( Z ‐score: −7). Ramachandran plot analysis confirmed 98.2% of residues in favored regions. The CASTp server identified Pocket 1 as the most viable active site (surface area: 377.747 Å 2 ; volume: 246.836 Å 3 ). Virtual screening and Molecular docking using DrugRep screened FDA‐approved, experimental, and Traditional Chinese Medicine (TCM) compounds. Among them, Dolutegravir (FDA; −9.9 kcal/mol), Indirubin‐5‐sulphonate (experimental; −10.5 kcal/mol), and Sauchinone (TCM; −10.5 kcal/mol) showed the highest binding affinities. The Absorptive, distributive, metabolic, excretory, and toxic (ADMET) analysis via SwissADME and STopTox predicted favorable pharmacokinetics and low toxicity. Molecular dynamics simulations using CABS‐Flex validated the stability of these ligand‐TK complexes. Overall, this integrative computational approach highlights TK as a viable antiviral target and identifies promising lead compounds for further validation. This study presents the first comprehensive computational framework identifying GTPV‐TK inhibitors, offering a robust foundation for developing novel anti‐capripoxviral therapies.

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