Computational investigation of potential natural compounds as inhibitor of Monkeypox virus cysteine proteinase

Riya Nalwa¹Anis Ahmad Chaudhary²Mandeep Chouhan¹Prashant Kumar Tiwari¹Saurabh Gupta³Hassan Ahmed RUDAYNI²Vivek Dhar Dwivedi^4,5Sanjay Kumar^1*

• ¹Sharda University, Greater Noida, India
• ²Imam Muhammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
• ³GLA University, Mathura, India
• ⁴Quanta Calculus, Greater Noida, India
• ⁵SIMATS Deemed University Saveetha Medical College and Hospital, Chennai, India

Introduction: Monkeypox is a serious viral illness that is rarely seen but is spread from person to person and from animals to humans. The Cysteine proteinase, an essential enzyme involved in the replication of the monkeypox virus (MPXV), is one of many possible therapeutic targets for MPXV. The primary function of this enzyme is to cleave the precursor polyprotein into the distinct proteins required for viral assembly. The aim was to develop potential drugs that can inhibit the proteinase and stop the spreading of the MPXV. Methods: The virtual screening, molecular docking, molecular dynamics simulation, and free binding energy calculations were used in order to explore the potential of 569 phytochemicals from a different variety of plants that could inhibit the proteinase of the MPXV. Results: Based on the docking score, the top four compounds (Unii-CQ2F5O6yiy, Lithospermic acid, Kaempferol, and Rhamnocitrin) displayed docking score values ranging from -9.5 to -7.4 kcal/mol and were used for further analysis. Out of these, Unii-CQ2F5O6yiy exhibited the docking score of -9.5 kcal/mol, indicated the highest binding to the proteinase. Unii-CQ2F5O6yiy had the most stable and consistent RMSD with <3 Å. Discussion: We identified top four phytochemicals exhibited better docking score than reference compound. Also, RMSD of protein in all the phytochemical complexes exhibited acceptable deviation except lithospermic acid, whereas atoms of Unii-CQ2F5O6yiy and Kaempferol in their docked complexes displayed less fluctuation than the reference compound (<5.4 Å). Conclusions: Hence, Unii-CQ2F5O6yiy could be used as potential antiviral agents for the management of Monkeypox virus. However, further experimental validation under in vitro and in vivo conditions is required to confirm its antiviral activity against MPXV.