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<p>Dengue infection is caused by an arboviral pathogen that has imposed life-threating risk on millions of people worldwide through its wide spectrum of symptoms with no clinically approved therapeutics available till date. The non-structural 3 (NS3) protein constitutes two domains namely amino terminal protease and carboxy terminal helicase. The protease and helicase are involved in cleaving the polyprotein to form the mature viral proteins and unwinding of the viral genome during replication respectively. The probable small molecule binding sites were predicted using CastP and the obtained data matched to existing literature evidences. Virtual screening of drugs from the DrugBank database, against these binding sites were conducted which led to selection of druggable ligands based on the binding affinity scores with subsequent MD simulation studies. Finally, two compounds, DB06237 (Avanafil) and DB11262 (Bisoctrizole) were selected for further studies based on computational analyses. ADMET profiling of these two compounds revealed their potential drug-like nature based on their physico-chemical properties. Advanced MD methods like ColDock simulation were also executed to estimate the spontaneous binding propensity of the two selected molecules with the entire NS3 protein. It was observed that both the molecules bound to the binding sites spontaneously as revealed from ColDock MD simulations. The final selected molecule was further subjected to extended MD simulation in order to study the binding dynamics of the molecule in the protein binding pocket. This study may provide an insight for utilizing small molecule inhibitors for the pharmacological development and repurposing of established drugs to curb the fatal consequences of dengue virus infection.</p>

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Repurposing of drug molecules targeting protease and helicase domain of Dengue virus NS3 protein: a virtual screening approach

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Dwaipayan Chaudhuri,
  • Shubhangi Chatterjee,
  • Satyabrata Majumder,
  • Kalyan Giri

摘要

Dengue infection is caused by an arboviral pathogen that has imposed life-threating risk on millions of people worldwide through its wide spectrum of symptoms with no clinically approved therapeutics available till date. The non-structural 3 (NS3) protein constitutes two domains namely amino terminal protease and carboxy terminal helicase. The protease and helicase are involved in cleaving the polyprotein to form the mature viral proteins and unwinding of the viral genome during replication respectively. The probable small molecule binding sites were predicted using CastP and the obtained data matched to existing literature evidences. Virtual screening of drugs from the DrugBank database, against these binding sites were conducted which led to selection of druggable ligands based on the binding affinity scores with subsequent MD simulation studies. Finally, two compounds, DB06237 (Avanafil) and DB11262 (Bisoctrizole) were selected for further studies based on computational analyses. ADMET profiling of these two compounds revealed their potential drug-like nature based on their physico-chemical properties. Advanced MD methods like ColDock simulation were also executed to estimate the spontaneous binding propensity of the two selected molecules with the entire NS3 protein. It was observed that both the molecules bound to the binding sites spontaneously as revealed from ColDock MD simulations. The final selected molecule was further subjected to extended MD simulation in order to study the binding dynamics of the molecule in the protein binding pocket. This study may provide an insight for utilizing small molecule inhibitors for the pharmacological development and repurposing of established drugs to curb the fatal consequences of dengue virus infection.