Free Energy Calculations on the Binding of Natural Latrunculins and Semi-synthetic Derivatives to G-Actin

Latrunculins are significant biological molecules isolated from Negombata species, characterized by a macrocyclic lactone ring and a 2-thiazolidinone moiety. In vitro experiments revealed that the latrunculins disrupt actin polymerization. Despite having a wide variety of biological activities, their direct therapeutic use is limited by cytotoxicity. However modified latrunculins show great potential to have a wide range of useful biological activities including related to Alzheimer's disease [1,2]. We have designed a few synthetically feasible analogs of Latrunculin B with intentions to have compounds with reduced toxicity and better binding. Both naturally available and newly designed molecules were subjected to induced fit docking into G-actin. Molecular dynamics simulations and binding free energy (BFE) calculations of G-actin and the latrunculins were carried out. The docking studies revealed the binding mode of latrunculin B and analogs and were helpful to suggest possible modifications to reduce the toxicity [3]. The BFE calculations agreed well with actin polymerization inhibition data demonstrating that the recently isolated oxalatrunculin B binds more weakly than latrunculins A and B to G-actin. The binding of the latrunculins to G-actin and details of the protein-ligand interactions explain the decrease in activity of oxalatrunculin B and semi-synthetic analogs, reduced inhibition which should be beneficial for avoiding general toxicity.

Acknowledgements: NIH National Center for Research Resources C06 RR-14503-01 and 5P20RR021929; National Science Foundation EPS-0556308. PRD is a University of Mississippi NIH CORE-NPN Natural Products Neuroscience Fellow. References: [1] Harms C, et al. (2004), Mol Cell Neurosci. 25: 69–82. [2] Fulga TA, et al. (2007), Nat Cell Biol, 9: 139–48. [3] Ahmed SA, et al. (2007), Org Lett, 9: 4773–4776.