Title:Introduction of Novel Drug Targets against Staphylococcus aureus and Proposing
Putative Inhibitors against Adenine N1 (m1A22)-tRNA Methyltransferase (TrmK)
using Computer-aided Drug Discovery
Volume: 29
Issue: 14
Author(s): Masoumeh Beig, Tahereh Ebrahimi, Narjes Noori Goodarzi, Sepideh Fereshteh, Mehri Habibi and Farzad Badmasti*
Affiliation:
- Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center
(MRC), Pasteur Institute of Iran, Tehran, Iran
Keywords:
Staphylococcus aureus, structure-based virtual screening, TrmK, Quinaldopeptin, ADMET, VRSA.
Abstract:
Background: Nowadays, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) and
vancomycin-resistant S. aureus (VRSA) strains has dramatically restricted the treatment options against this
microorganism.
Aim: In this study, we aimed to discover new drug targets and inhibitors against S. aureus.
Methods: This study consists of two major sections. In the upstream evaluation, after a comprehensive coreproteome
analysis, essential cytoplasmic proteins with no similarity to the human proteome were selected. Then the
S. aureus metabolome-specific proteins were selected, and novel drug targets were identified using the DrugBank
database. In the downstream analysis, a structure-based virtual screening approach was performed to reveal potential
hit compounds against adenine N1 (m1A22)-tRNA methyltransferase (TrmK) using the StreptomeDB library
and AutoDock Vina software. The compounds with a binding affinity > -9 kcal/mol were analyzed based on ADMET
properties. Finally, the hit compounds were selected based on Lipinski’s rule of five (RO5).
Results: Three proteins, including glycine glycosyltransferase (FemA), TrmK, and heptaprenyl pyrophosphate
synthase subunit A (HepS1), were selected as feasible and promising drug targets based on PDB file availability
and their essential role in the survival of the S. aureus. Finally, seven hit compounds, including Nocardioazine_
A, Geninthiocin_D, Citreamicin_delta, Quinaldopeptin, Rachelmycin, Di-AFN_A1 and Naphthomycin_
K were introduced against the binding cavity of TrmK, as a feasible drug target.
Conclusion: The results of this study provided three feasible drug targets against S. aureus. In the following,
seven hit compounds were introduced as potential inhibitors of TrmK, and Geninthiocin_D was identified as
the most desirable agent. However, in vivo and in vitro investigations are needed to confirm the inhibitory effect
of these agents on S. aureus.
