In silico design of novel SAM analogs as potential inhibitors against N2G966 16s rRNA methyltransferase (RsmD)

Abstract

Introduction: Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) has its natural history tracing back to 70,000 years. Latent M.tb infection is the reservoir of the TB epidemic. M.tb is becoming more prevalent and acquiring multidrug resistance among the first line antibiotics. Methods: Methylation is one of the main mechanisms through which bacteria develop resistance, hence targeting methyltransferases provides the opportunity to achieve two-birds-with-one-stone: a) antibiotic: inhibiting the translation activity and b) anti-resistance: eliminating methylation as a mode of resistance. Currently, none of the known drugs or lead molecules are targeting the methyltransferases in general, rRNA Small Subunit Methyltransferase D (RsmD) family in particular in M.tb Species. Results and Conclusion: S-Adenosyl-L-methionine(SAM), is known as the universal donor of methyl group which is an indispensable cofactor for proper functioning of SAM dependent methyltransferases. This in silico study attempts to design and develop novel SAM-analog inhibitors against RsmD which in turn affects the growth and survival of M.tb in TB patients. The SAM-analogs were designed, after careful study and analysis of RsmD pharmacophore and SAM binding properties. The functional groups such as amide, amine, acetamide, formamide, hydroxyl, fluorine, iodine, bromine were used to design novel analogs with the aim to improve the binding of analog with RsmD. The analogs that gave better docking scores followed by favourable binding affinities and ADMET properties than native SAM were ranked. Among the library of SAM analogs, the top two analogs with IDs: SAM_172 and SAM_153 need testing and validation for their efficacy through in vitro and in vivo studies.