Title:In silico Design of Novel SAM Analogs as Potential Inhibitors Against
N2G966 16s rRNA Methyltransferase (RsmD)
Volume: 20
Issue: 12
Author(s): Muthu Raj Salaikumaran and Venkata Laxmi Siva Prasad Burra*
Affiliation:
- Centre for Advanced Research and Innovation in Structural Biology of Diseases, K L E F University, Vaddeswaram, Andhra Pradesh 522 502, India
Keywords:
Tuberculosis, S-Adenosyl-L-Methionine, SAM-analogs, methyltransferases, rRNA small subunit methyltransferase D, pharmacophore.
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, no known drugs or lead molecules are targeting the methyltransferases, in general, and rRNA
Small Subunit Methyltransferase D (RsmD) family, in particular, in M.tb species.
Results and Discussion: S-Adenosyl-L-methionine(SAM) is known as the universal donor of a methyl
group which is an indispensable cofactor for the 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, and 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.
Conclusion: 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.