Planta Med 2008; 74 - P-62
DOI: 10.1055/s-2008-1075258

Actin-binding Comparisons of the Marine Natural Product Latrunculin B with Natural and Semi-synthetic Latrunculin B Analogs

JJ Bowling 1, PR Daga 2, S Odde 2, SA Ahmed 3, MK Mesbah 3, DT Youssef 3, S Kudrimoti 1, SI Khalifa 3, RJ Doerksen 2, 4, MT Hamann 1, 4
  • 1Department of Pharmacognosy, The University ofMississippi, University, Mississippi, 38677, USA
  • 2Department of Medicinal Chemistry, The University ofMississippi, University, Mississippi, 38677, USA
  • 3Department of Pharmacognosy, Faculty of Pharmacy, Suez Canal University, Ismalia, Eygpt
  • 4National Center for Natural Products Research, The University of Mississippi, University, Mississippi, 38677, USA

Inhibition of actin polymerization by the marine natural product latrunculin A has been quantified [1], whereas the inhibition of its geometric isomer latrunculin B (1) has only been estimated [2]. In this study, measurement of the inhibition of actin polymerization is used to compare the relative actin binding of 1 to a recently reported [3] natural analog Oxalatrunculin B (2) and two semi-synthetic analogs 3 and 4. Docking and molecular dynamics followed by MM-PBSA free energy calculations predicted affinity in the following order 1 >> 2 > 3 ≈ 4. The docking poses showed that 3 and 4 would not be able to fit well into the active site of G-actin due to steric clashes. The EC50 of 1 was determined to be 2.56 µM, 2 was not as effective at the same concentration and both semi-synthetic analogs were ineffective at the highest tested concentration (15 µM) reinforcing the modeling predictions of binding affinity. Acknowledgements: Thank you to the Egyptian Environmental Affairs Agency for facilitating sponge and sample collection and R. van Soest (University of Amsterdam) for sponge taxonomy. This work was made possible through the support of the U.S.-Egypt Science and Technology joint fund project number BIO8-002-013, National Institutes of Health (NIAID) 1RO1AI36596, NIH National Center for Research Resources CO6 RR-14503-01 and National Science Foundation EPS-0556308. References: [1] Coué M, et al. (1987) FEBS Lett. 213(2): 316–8. [2] Spector I, et al. (1983) Science 219(4584): 493–5. [3] Ahmed S, et al. (2007) Org Lett. 9(23): 4773–6.