In Silico Screening, Analysis and Design of Potential Inhibitors Against RsmD for Treating Tuberculosis

Mycobacterium tuberculosis (M.tb) causes TB and has ever since remained as a major global health burden because of increased rate of antibiotic resistance, an alert raised by WHO. RsmD is involved in the proper functioning of protein translation and protecting the organism (parasite) from drug action through methylation which is one of the most common epigenetic modifications adopted by the parasite referred to as drug resistance. Hence, targeting (RsmD) gives the opportunity to kill two-birds-with-one-stone: a) antibiotic role of drug and b) Anti-drug resistance. To discover the potential lead compounds against RsmD, a curated small molecule database of nucleoside mimetics from ASINEX were screened implementing Lipinski rule of five, further filtered to obtain compounds with molecular weights (MW) ranging between 350 Da - 450 Da. These compounds were docked with RsmD using CDOCKER of DS2022. Compounds with good CDOCKER score and favorable energies were further subjected to ADMET prediction, TOPKAT studies, molecular dynamics simulations and MM-PBSA binding energy calculations. Out of 4507 compounds 100 compounds were selected with CDOCKER energies ranging from -33 to -58 kcal/mol. On subjecting the 100 compounds to ADMET analysis and TOPKAT properties only 10 compounds were ensured as safe, non-toxic, non-carcinogenic and non-irritants. The top three leads, ASXNAID_3215, ASXNAID_3187 and ASXNAID_3182, are learnt to be easy to synthesize and are computationally verified and now demand for in vitro and in vivo evaluation and testing.