Computational investigation of marine bioactive compounds reveals frigocyclinone as a potent inhibitor of Kaposi’s Sarcoma Associated Herpesvirus (KSHV) targets

In the present study, in silico analysis was employed to identify the action of marine bioactive compounds against KSHV targets. Virulence factor analysis of KSHV from literature review, three proteins LANA1, vIRF3/LANA2 and PF-8 were identified as putative drug targets. The quality of protein structures play a significant role in the experimental structure validation and prediction, where the predicted structures may contain considerable errors was checked by SAVES v5.0 servers. By virtual screening four potential bioactive compounds Ascorbic acid, Salicylihalamide A, Salicylihalamide B and Frigocyclinone were predicted. One of the potential compounds of Frigocyclinone has acting against KSHV proteins. Hence, determined as the good lead molecule against KSHV. Molecular dynamic simulation studies revealed the stability of LANA1- Frigocyclinone complex and it could be a futuristic perspective chemical compound for Kaposi’s sarcoma.

Salicylihalamide A Inhibits the V0Sector of the V-ATPase through a Mechanism Distinct from Bafilomycin A1

The newly identified specific V-ATPase inhibitor, salicylihalamide A, is distinct from any previously identified V-ATPase inhibitors in that it inhibits only mammalian V-ATPases, but not those from yeast or other fungi (Boyd, M. R., Farina, C., Belfiore, P., Gagliardi, S., Kim, J. W., Hayakawa, Y., Beutler, J. A., McKee, T. C., Bowman, B. J., and Bowman, E. J. (2001)J. Pharmacol. Exp. Ther.297, 114–120). In addition, salicylihalamide A does not compete with concanamycin or bafilomycin for binding to V-ATPase, indicating that it has a different binding site from those classic V-ATPase inhibitors (Huss, M., Ingenhorst, G., Konig, S., Gassel, M., Drose, S., Zeeck, A., Altendorf, K., and Wieczorek, H. (2002)J. Biol. Chem.277, 40544–40548). By using purified bovine brain V-pump and its dissociated V1and V0sectors, we identified the recognition and binding site for salicylihalamide to be within the V0domain. Salicylihalamide does not inhibit the ATP hydrolysis activity of the dissociated V1-ATPase but inhibits the ATPase activity of the holoenzyme by inhibiting the V0domain. Salicylihalamide causes a dramatic redistribution of cytosolic V1from soluble to membrane-associated form, a change not observed in cells treated with either bafilomycin or NH4Cl. By synthesizing and characterizing a series of salicylihalamide derivatives, we investigated the structural determinants of salicylihalamide inhibition in terms of potency and reversibility, and used this information to suggest a possible binding mechanism.