The procedure used in this study had been defined in a previous study [1] and necessary permission was obtained to reproduce it here. (see Procedure in the Supplementary Files)
The three-dimensional structure of SARS-CoV2 main protease with inhibitor was downloaded from Protein Data Bank (PDB id: 6WTT) [2].
Figure 1: SARS-CoV2 main protease 6WTT tertiary structure visualised in UCSF Chimera [3] software. Ligands are marked in red.
For molecular docking, three-dimensional structures of 841 compounds were obtained from Zinc15 database [4]. The compounds constituted only those which were approved by FDA. This step was taken so as to facilitate easy availability after clinical trials.
6WTT structure constitutes three chains A, B and C. In order to obtain the active site of the receptor, Drug Discovery Studio software [5] was utilised to find the interactions between the inhibitor and amino acids. These amino acids would serve as the desired target in molecular docking.
PyRx software which includes within itself Autodock Vina and Open Babel was used for molecular docking [6][7][8]. Since all three chains and their corresponding ligands were similar, only one chain was used as the target. The chain was extracted from the entire structure and it was cleared of all ligands and water molecules. The cleaned structure was converted into an Autodock macromolecule by addition of hydrogen atoms and partial charges. The ligand compounds from Zinc15 database were brought to the minimum energy configuration and were converted in Autodock ligands by using Open Babel.
The Vina search space parameters were set to the following values so as to include all target amino acids:
center_x = 2.92116253491
center_y = 26.9617112837
center_z = -10.4416644449
size_x = 18.1979693434
size_y = 19.9112571778
size_z = 28.9662108454
Exhaustiveness was set to 4 for faster computation. All the above operations were performed on a Windows 10 64-bit operating system. The entire docking took about 8 hours with 100% CPU utilization.
Figure 2: Receptor chain is represented in lines. Target amino acids are highlighted in pink. Cuboid indicates the restricted search space including all target amino acids.
The results of docking obtained were sorted on basis of binding affinity. Lower the binding affinity, more stringer is the interaction. For every ligand configuration, only those which had root mean square deviation (RMSD) value 0.0 were chosen. The interactions of receptor with every ligand was visualized using Drug Discovery Studio. The number of desired target amino acids interacted were noted and final result was obtained. If any ligand showed unfavourable interactions, it was excluded to improve accuracy of the study.