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QSAR, homology modeling, and docking simulation on SARS-CoV-2 and pseudomonas aeruginosa inhibitors, ADMET, and molecular dynamic simulations to find a possible oral lead candidate



Background:

In seek of potent and non-toxic iminoguanidine derivatives formerly assessed as active Pseudomonas aeruginosa inhibitors, a combined mathematical approach of quantitative structure-activity relationship (QSAR), homology modeling, docking simulation, ADMET, and molecular dynamics simulations were executed on iminoguanidine derivatives.


Results:

The QSAR method was employed to statistically analyze the structure-activity relationships (SAR) and had conceded good statistical significance for eminent predictive model; (GA-MLR: Q2LOO = 0.8027; R 2 = 0.8735; R 2ext = 0.7536). Thorough scrutiny of the predictive models disclosed that the Centered Broto-Moreau autocorrelation – lag 1/weighted by I-state and 3D topological distance-based autocorrelation-lag 9/weighted by I-state oversee the biological activity and rendered much useful information to realize the properties required to develop new potent Pseudomonas aeruginosa inhibitors. The next mathematical model work accomplished here emphasizes finding a potential drug that could aid in curing Pseudomonas aeruginosa and SARS-CoV-2 as the drug targets Pseudomonas aeruginosa. This involves homology modeling of RNA polymerase-binding transcription factor DksA and COVID-19 main protease receptors, docking simulations, and pharmacokinetic screening studies of hits compounds against the receptor to identify potential inhibitors that can serve to regulate the modeled enzymes. The modeled protein exhibits the most favorable regions more than 90% with a minimum disallowed region less than 5% and is simulated under a hydrophilic environment. The docking simulations of all the series to the binding pocket of the built protein model were done to demonstrate their binding style and to recognize critical interacting residues inside the binding site. Their binding constancy for the modeled receptors has been assessed through RMSD, RMSF, and SASA analysis from 1-ns molecular dynamics simulations (MDS) run.


Conclusion:

Our acknowledged drugs could be a proficient cure for SARS-CoV-2 and Pseudomonas aeruginosa drug discovery, having said that extra testing (in vitro and in vivo) is essential to explain their latent as novel drugs and manner of action.


Supplementary information:

The online version contains supplementary material available at 10.1186/s43141-022-00362-z.


Keywords:

ADMET; Homology modeling; MD simulations; Molecular docking; Pseudomonas aeruginosa; QSAR; SARS-CoV-2; and iminoguanidine derivatives.



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