title: Treponema pallidum putative novel drug target identification and validation: rethinking syphilis therapeutics with plant-derived terpenoids.
abstract: Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide.
authors: Department of Biochemistry, Centre of Excellence in Bioinformatics, Bioinformatics Infrastructure Facility, University of Lucknow , Lucknow, U.P., India .
authors: Upendra N
authors: UN
authors: Dwivedi
authors: Sameeksha
authors: S
authors: Tiwari
authors: Priyanka
authors: P
authors: Singh
authors: Swati
authors: S
authors: Singh
authors: Manika
authors: M
authors: Awasthi
authors: Veda P
authors: VP
authors: Pandey
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008958:Models, Molecular; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport; D020543:Proteome; D013587:Syphilis / Q000188:drug therapy / Q000382:microbiology; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D014210:Treponema pallidum / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010936:Plant Extracts; D020543:Proteome; D013729:Terpenes