Recent studies on the bio-potency of Sansalvamide A derivatives show promising properties against pancreatic, colon, breast, prostate, and melanoma cancers. Recent NCI panels have also proven potency on leukemia, thus a more detailed analysis of the structural features within the macrocycles is needed to explore further roles of the molecules. Sansalvamide A (San A) is a marine fungal product that was discovered by William Fenical. Through structural manipulation of peptide derivatives based on structure-activity relationship (SAR) and 2-D NMR, valuable trends arise to provide a systematic means of controlling bio-potency. Through the use of various biological assays as well as computational resources it is possible to analyze the effect of such conformational changes and gain insight into the development of more potent compounds.

Multiple derivatives of the San A scaffold were synthesized and their activity on a pancreatic cancer cell line PL-45 and the colon cancer cell line HCT-116 is reported here. Then, using MacroModel within Maestro, we have validated the preferred conformation of many San A derivatives. Using Monte Carlo methods as well as conformational constraint and limiting electrostatic and steric qualifications, a pool of conformers was created. By arranging the lowest energy conformer within NAMFIS and using 2D NMR experiments NOESY and ROESY predictive studies of the proposed protein target of the derivatives are described. By performing pull-down assays we have determined that the protein target of these derivatives is Hsp90, and therefore computational validation combined with incorporation of the co-crystal structure of Hsp90-drug can be used to determine the active conformation of the molecule when bound to Hsp90. This crystalline matrix will then be analyzed using NAMFIS, a NMR based modeling program, to create a dynamical picture of the Sansalvamide A derivatives. Future potent derivatives can then be predicted using this hybrid computational/experimental approach.