Molecular dynamic simulation studies of mutated Indinavir and Hydroxychloroquine-SARS-CoV2 protease complexes using Gromacs package

Molecular dynamics simulation is a method for analyzing atomic level movements which can evaluate protein and drug interactions with better accuracy. The calculations running behind this dynamic evolution are computationally expensive to simulate. Using the GROMACS tool under the XSEDE high performance computing platform, this task can be performed easily. From the initial bioinformatics study, Indinavir and Hydroxychloroquine were chosen as primary candidates amongst 6 lead compounds which are currently under research as SARS-CoV2 protease inhibitors. The study was focussed on analysing the efficacy of these two drugs under mutation effects in the protease ligand binding region. Both site directed as well as random substitution mutations were carried out in the ligand binding region. While the site directed mutations were performed based on altering the residues which were found unconserved, random mutation were applied using an in-house python code which simulated nucleotide substitutions for a total of 200 mutation cycles. Statistical testing showed both results pointing towards a similar trend of lower variance in the Hydroxychloroquine-protease complex binding affinity. Besides a constant binding capability of this drug towards mutant protease, an almost similar binding affinity to Indinavir points towards its effectiveness under an evolving SARS-CoV2 main protease. The preliminary results have been published as a pre-print (https://doi.org/10.21203/rs.3.rs-22082/v1). We wish to run molecular dynamics simulation to further validate this hypothesis, which otherwise cannot be deduced from docking results alone. The proposed study can increase our understanding towards the use of Hydroxychloroquine and similar drugs towards rapidly evolving viral infection states.