In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes

Abstract

Streptococcus pyogenes is a significant pathogen that causes skin and upper respiratory tract infections and non-suppurative complications, such as acute rheumatic fever and post-strep glomerulonephritis. Multidrug resistance has emerged in S. pyogenes strains, making them more dangerous and pathogenic. Hence, it is necessary to identify and develop therapeutic methods that would present novel approaches to S. pyogenes infections. In the current study, a subtractive proteomics approach was employed to core proteomes of four strains of S. pyogenes using several bioinformatic software tools and servers. The core proteome consists of 1324 proteins, and 302 essential proteins were predicted from them. These essential proteins were analyzed using BLASTp against human proteome, and the number of potential targets was reduced to 145. Based on subcellular localization prediction, 46 proteins with cytoplasmic localization were chosen for metabolic pathway analysis. Only two cytoplasmic proteins, i.e., chromosomal replication initiator protein DnaA and two-component response regulator (TCR), were discovered to have the potential to be novel drug target candidates. Three-dimensional (3D) structure prediction of target proteins was carried out via the Swiss Model server. Molecular docking approach was employed to screen the library of 1000 phytochemicals against the interacting residues of the target proteins through the MOE software. Further, the docking studies were validated by running molecular dynamics simulation and highly popular binding free energy approaches of MM-GBSA and MM-PBSA. The findings revealed a promising candidate as a novel target against S. pyogenes infections.

Pharmacophore modelling based virtual screening and molecular dynamics identified the novel inhibitors and drug targets against Waddlia chondrophila

“…Same technique was used by researchers to identify potential targets against Streptococcus pneumoniae Strain D39 71 , Fusobacterium nucleatum 72 , Streptococcus pyogenes 48 , and shigella sonnei 73 . Hence, the novel drug targets discovered in this work should be very helpful in the drug therapeutic industry for finding inhibitors and devising new drug formulations to combat W. chondrophila infections, albeit more experimental research are required to confirm these drug targets.…”

“…This technique is a well-known, reliable, and potent analytical approach. The binding free energy of specific MD snapshots was calculated using the Amber tool 20 MMGBSA script (py) 48 – 50 .…”

Taxonomic Assignment-Based Genome Reconstruction from Apical Periodontal Metagenomes to Identify Antibiotic Resistance and Virulence Factors

“…Here, we proposed some newer members of bacteria from our study, which displayed shallow ANI values. Further, in our core proteome analysis, 11 core orthogoups were identified among all MAGs belonging to the two-component system, ATPase transporter, transcriptional regulator and autolysin, which can be targeted for antimicrobial drug and vaccine development for treating keystone crucial species that are predominantly responsible for specific endodontic infection types [ 64 ].…”

Inhibition of Replication Fork Formation and Progression: Targeting the Replication Initiation and Primosomal Proteins

“…Furthermore, specific inhibitors of B. anthracis primase identified with the coupled colorimetric primase-pyrophosphatase assay also failed to show in vivo activity, due to an inability to penetrate the bacterial envelope [119]. More recent studies applying molecular docking approaches [121,136] and/or fragment-based screens [117,122] have identified inhibitors with their activity yet to demonstrate in vivo. Multi-target approaches increase the potential for identification of lead compounds [128].…”