Integrated Subtractive Proteomics and Molecular Docking Reveal a Novel Therapeutic Target and Tuberosin as a Lead Phytochemical Against Streptococcus pneumoniae
Ahaana Jain
13/08/2026
Streptococcus pneumoniae remains a leading cause of community-acquired pneumonia, meningitis and invasive pneumococcal disease, and rising antimicrobial resistance has undermined existing therapeutics, creating an urgent need for novel, microbiome-sparing drug targets. We applied an integrated, six-stage computational pipeline—combining subtractive proteomics, homology modelling and structure-based virtual screening—to the hypothetical proteome of S. pneumoniae strain OTU45 (GenBank CP113114.1). Of 282 hypothetical proteins, sequential filtering on physicochemical druggability, VaxiJen-predicted non-antigenicity and zero BLASTp identity to ten representative gut-commensal proteomes shortlisted 70 candidates (24.8%). TMHMM 2.0 and InterProScan/PHOBIUS topology prediction, combined in a seven-criterion composite scoring matrix (max 35), identified OTU45_03800, a six-pass integral membrane protein of unknown function, as the top-ranked target (score 30/35; GRAVY +0.985; VaxiJen 0.293; 28.19 kDa). A homology model of OTU45_03800 built in SWISS-MODEL was docked in AutoDock Vina (via PyRx) against 211 ADMET-compliant phytochemicals drawn from an initial library of 523 natural products screened using Lipinski, Ghose, Veber, Egan and Muegge drug-likeness filters and SwissADME-based pharmacokinetic profiling. Nineteen compounds achieved binding energies ≤ −8.1 kcal/mol; although nordihydrotoxiferine, dracorubin and morellin bound most strongly (−9.6 to −9.4 kcal/mol), each carried disqualifying ADMET liabilities. Integrated binding-affinity and drug-likeness ranking identified Tuberosin, a pterocarpan-class phytochemical (−8.5 kcal/mol), as the overall lead: it satisfied all five drug-likeness filters with zero violations, showed high predicted gastrointestinal absorption and blood–brain-barrier permeability, and engaged the OTU45_03800 binding cavity with no unfavourable steric contacts. γ-Galbacin, Hispaglabridin-B, Berbamine and Sesamin constituted a ranked series of secondary candidates. This study nominates OTU45_03800 as a previously unexplored, computationally validated antibacterial target and Tuberosin as a developable natural-product lead, providing a rational framework for next-generation anti-pneumococcal drug discovery pending experimental validation.