Druggable proteins of Alistipes reveal promising antimicrobial targets against chronic intestinal inflammation

Saman Sohail¹Ayesha Wisal¹Sobia Rana²Abid Khan - Rao Muhammad³Asad Ullah¹Farooq-Ahmad Khan⁴Muhammad Irfan²Muhammad Imran^5*Carvalho, P.V.S.D^6*Renato Rozental^6*Farzana Shaheen^2,4*Hassan Syed Shah^2*

• ¹Department of Chemistry, Islamia College University, Peshawar, Khyber Pakhtunkhwa, Pakistan
• ²Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences , University of Karachi, Karachi, Pakistan
• ³Sindh Institute of Urology and Transplantation, Karachi, Sindh, Pakistan
• ⁴Hussain Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Punjab, Pakistan
• ⁵Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia
• ⁶Center for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, Rio de Janeiro, Brazil

The genus Alistipes consists of anaerobic, gram-negative bacteria with 13 species that colonize the entire gastrointestinal tract and are a serious health concern. They contribute to gut dysbiosis, intestinal inflammation, colorectal cancer, and depression. To explore potential therapeutic targets and inhibitors, we filtered the core genome of Alistipes strains through subtractive genomics for non-host homology, gene essentiality, PPI, KEGG pathways, virulence, cellular localization, and druggability. The potential targets were docked against two drug-like libraries (ZINC, n = 11,993) and TCM (n = 36,043). ADMET profiling for best hits and MD simulation for apo/complex structures were performed, followed by physicochemical and pharmacokinetic evaluation and complex stabilities. A set of 39 potential proteins was drastically reduced to only two targets after sequential data mining. The 3D structures of the selected targets (LpxA and KdsB) revealed good druggability scores. The top hits (ZINC85530940, ZINC05161112, ZINC95911713, and ZINC05566415) for both targets showed maximum H-bond interactions. The RMSD and RMSF values exhibited compactness with minimum fluctuation in ligand-bound complexes. The β-factor of ZINC05161112 at 327 th residue and 352 nd residue exhibited higher thermal instability, consistent with the RMSF results. The globularity of the complexes and apo structures remained consistent, whereas the LpxA complexes exhibited lower solvent-accessible surface area. For the KdsB, the surface area for ZINC5566415 increased significantly, with a steep decrease for ZINC95911713, establishing rather stable protein-ligand complexes. The results highlight the importance of identifying novel inhibitors and therapeutic targets. They are crucial for establishing better treatment regimes for human health and to aid in controlling the pathogenicity of Alistipes species.