title: Differential binding of latrunculins to G-actin: a molecular dynamics study.
abstract: Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculin A (1), latrunculin B (2), 16-epi-latrunculin B (3), and latrunculin T (4) were isolated from the Red Sea sponge Negombata magnifica. In the present study, after testing compounds 2-4 for cytotoxic activity, they were docked into the crystal structure of G-actin and subjected to binding energy calculation and a 20 ns MD simulation. The modeling study shows that latrunculins binding depends on both hydrophobic interaction of the macrocycle as well as H bonding of the thiazolidinone ring with Asp157 and Thr186. It was noticed that epimerization at C16 of latrunculin B was well tolerated as it could form an alternative H bonding network. However, opening of the macrocyclic ring deteriorates the actin binding due to reduced hydrophobicity. MD simulation showed that latrunculin B (2) possesses a more significant stabilizing effect on G-actin than latrunculin T (4) and could efficiently hinder the flattening transition of G-actin into F-actin. These findings could explain, at the molecular level, the impact of epimerization and macrolide ring-opening on latrunculins activity, an issue that has not been addressed before. Also, the study gives insights into the mechanism of cytotoxicity of diverse latrunculins and provides direction for future lead optimization studies.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University , Ismailia, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Helal
authors.forename: Sherief
authors.initials: S
authors.lastname: Khalifa
authors.forename: Safwat
authors.initials: S
authors.lastname: Ahmed
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D009068:Movement; D011161:Porifera; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D053778:Thiazolidines / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000199:Actins; D053778:Thiazolidines