ஜர்னல் ஆஃப் புரோட்டியோமிக்ஸ் & பயோ இன்ஃபர்மேடிக்ஸ்
திறந்த அணுகல்

சுருக்கம்

Inhibitor Design for VacA Toxin of Helicobacter pylori

Pasala Chiranjeevi, Sandeep Swargam, Natarajan Pradeep, Kanipakam Hema, Katari Sudheer Kumar, Nalamolu Ravina Madhulitha and Amineni Umamaheswari

Vacuolating cytotoxin autotransporter is secreted by Helicobacter pylori and considered to be an important unique virulence factor in the pathogenesis. VacA toxin is a 140 kDa protoxin contains 1287 amino acids, undergoes N- and C-terminal cleavage to yield a mature 88 kDa toxin consisting of 1-821 residues (p88). Further, matured toxin is crucial to function as active VacA and adheres onto plasma membrane to form anionic channels lead to pathogen entry, formation of vacuoles apt for making colonies in gastric mucosa of humans. As a result, the chronic sequelae such as intolerable gastritis, peptic ulcers, MALT-lymphoma and adenocarcinoma were caused. VacA toxin has attained great attention and selected as drug target to design potential inhibitors. Crystal structure of p55 domain of VacA was prepared and minimized using protein preparation wizard in Maestro v9.8. A grid was generated on p33 binding site of p55 domain important for VacA adherence onto epithelial membrane. Rigid receptor docking was performed with prepared in-house library of one million compounds using Glide v6.3. Subsequently, QPLD and IFD with Prime/MM–GBSA were carried out to predict the binding free-energy scores. QPLD docking complex has binding free energy (ΔG) of -48.286 kcal/mol. The docked complex showed stability with one hydrogen bonds, three water mediated interactions with lowest energy during 50 ns molecular dynamic simulations run. Thus, the proposed leads represent novel valuable starting point in the development of inhibitor to VacA.