Screening Possible Drug Molecules for Covid-19: A Computational Study based on Docking Studies & Molecular Dynamics to Design New Inhibitor Candidates

Manos C. Vlasiou*and Kyriaki S. PafitiDepartment of Life and Health Sciences, Pharmacy Program, University of Nicosia, [email protected]

After the Covid-19 pandemic and the aggressively infection control measures taken by the governments in the whole world, the need for a rapid pharmaceutical solution was more than necessary. The computer aided chemistry and molecular docking is a rapid tool to drug screening and investigation. Moreover, more metal-based drugs are tested daily by research institutes for their antiviral activity. Here, we used theoretical studies on previously published biological active complex molecules of vanadium as an example of evaluating possible drug candidates before entering the laboratory. Our findings suggest that theoretical investigation should always precede on drug discovery.

To create 2D and 3D structures of the ligand molecules, Chem3d Pro 12.0 and AVOGADRO 1.90.0 software programmes were used. Ligand optimisations were done by ORCA 4.1.1 software while ligands and receptor preparation studies were done by Chimera 1.14. Molecular docking studies were carried out by Autodock 4.2 and docking results were analysed by Chimera 1.14 program. Additionally, calculations on docking studies performed using iGEMDOCK 2.1 software. BSA, 6M03, 6M71 and 6YI3 coded crystal structures were selected from Protein Data Bank (www.rcsb.org). Ligand molecules were collected by literature.

Docking analyses showed that VXn coded ligand has the best binding score among all ligands with BSA protein,followed by Xn with a binding freeenergy of−108.72 kcal/mol. It makes hydrogen bonds with ASP108, PRO146,TYR147 and ILE455 (four H bonds), and also interacts with BSA with Vander Waals forces with a binding free energy of −93.23 kcal/mol. Regarding the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein (6YI3) the molecule Vbicahhas a binding free energy of-108.88 kcal/mol, followed by VXn with -105.23kcal/mol.Continuing with SARS-COV-2 RNA-dependent polymerase (6M71) starting with the ligand molecule with the highest affinity to the protein, Vbicah is the first with -102.66 kcal/mol followed by Vtocdea -98.91 Kcal/mol,Vtocdpa -97.06 Kcal/mol, Xn -96.03 Kcal/mol, VXn -93.64 Kcal/mol and finally Vbdea with -86.47 Kcal/mol.

In this study we performed several theoretical studies on vanadium complexes with biological activity from the literature. Based on that,we designed a new one the VXn molecule that showed similar activity with Vtocdea. We used computational chemistry methods to take valuable information of the molecules and performed molecular docking studies onCovid-19 related structures. Knowing from literature that Vtocdea exhibits the highest biological activity having at the same time the least toxicity in healthy cells, we conclude that these techniques should be used by the scientific community to save time and money on the fight against Covid-19 and take these valuable information in order to discover novel drug therapies with high effectiveness and the least toxicity.