A ClpP protein model as tuberculosis target for screening marine compounds

ATP-dependent Clp protease (ClpP) is a core unit of a major bacterial protease complex employing as a new attractive drug target for that isolates, which are resistant to antibiotics. Mycobacterium tuberculosis, a gram-positive bacterium, is one of the major causes of hospital acquired infections. ClpP in Mycobacterium tuberculosis is usually tightly regulated and strictly requires a member of the family of Clp-ATPase and often further accessory proteins for proteolytic activation. Inhibition of ClpP eliminates these safeguards and start proteolytic degradation. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death. In order to inhibit Clp protease, at first three dimensional structure model of ClpP in Mycobacterium tuberculosis was determined by comparative homology modeling program MODELLER based on crystal structure of the proteolytic component of the caseinolytic Clp protease (ClpP) from E. coli as a template protein and has 55%sequence identity with ClpP protein. The computed model's energy was minimized and validated using PROCHECK to obtain a stable model structure and is submitted in Protein Model Database (PMDB-ID: PM0075741). Stable model was further used for virtual screening against marine derived bioactive compound database through molecular docking studies using AutoDock 3.05. The docked complexes were validated and enumerated based on the AutoDock Scoring function to pick out the best marine inhibitors based on docked Energy. Thus from the entire 186 Marine compounds which were Docked, we got best 5 of them with optimal docked Energy (Ara-A: -14.31 kcal/mol, Dysinosin C: - 14.90kcal/mol, Nagelamide A: -20.49 kcal/mol, Strobilin: -8.02 kcal/mol, Manoalide: -8.81 kcal/mol). Further the five best-docked complexes were analyzed through Python Molecular Viewer software for their interaction studies. Thus from the Complex scoring and binding ability its deciphered that these Marine compounds could be promising inhibitors for ClpP as Drug target yet pharmacological studies have to confirm it.