Subtractive Genomics and Drug Repurposing Strategies for Targeting Streptococcus pneumoniae: Insights from Molecular Docking and Dynamics Simulations

Sanchaita Rajkhowa ^1* Borakha Bura Gohain ¹ Bhaskar Mazumder ¹ Sami Al HUSSAIN ² Magdi E. A. Zaki ^2*

• ¹ Dibrugarh University, Dibrugarh, India
• ² Imam Muhammad ibn Saud Islamic University, Riyadh, Saudi Arabia

Streptococcus pneumoniae, a Gram-positive bacterium, causes infections such as meningitis, pneumonia, otitis media, sinusitis, and conjunctivitis. Rising antibiotic resistance necessitates the identification of effective drug targets. Thus, this study aimed to identify therapeutic targets against S. pneumoniae using an in silico subtractive genomics approach. In this study, out of the 2,027 proteins from the S. pneumoniae genome, around 2,000 were identified as non-homologous in the human genome through the use of CD-HIT and BLASTp. The Database of Essential Genes (DEG) identified 48 essential genes, while 21 were obtained after considering human gut microflora.Protein-protein interaction analyses identified gpi, fba, rpoD, and trpS as the primary hub genes, while gene ontology (GO) studies uncovered 20 pathways associated with these targets. Due to the lack of a crystal structure, the potential target was further modeled. A virtual screening of 2,509 FDA-approved compounds utilizing various in silico methods on the modeled protein revealed Bromfenac as the leading candidate, exhibiting a binding energy of -26.335 ± 29.105 kJ/mol. Bromfenac when conjugated with AuAgCu2O nanoparticles is previously reported to possess antibacterial and anti-inflammatory properties, disrupting bacterial membranes and releasing metal ions. Therefore, it can be considered as a potential repurposed drug against S. pneumoniae, with further experimental validation. This study's methodology also indicates that such an approach could facilitate the repurposing of drugs targeting proteins that are absent in the host but are essential for the pathogen.