Computational Design and Docking of Hamigeromycin B Natural Product Derivatives in 26 Human Kinases

Abstract

Hamigeromycin B analogs are synthetic natural product derivatives with potential for mediating signal transduction in human kinases. To study potential activity, 11 Hamigeromycin analogs were constructed using MOE 2020 and optimized using AMBER14:EHT. The analogs were docked into 26 human kinase structures obtained from the Protein Data Bank using the Docking module of MOE 2020. The docking sites in each kinase were targeted using the Protein Frustratometer and Evolutionary Trace to characterize the energetics and evolutionary importance of amino acids for contributions to binding. The lowest binding free energy scores were used to determine the best binding and orientation of each analog. The data suggests that five kinases are potential targets. New compounds for study were computationally designed by modification of functional groups in the original analogs. All compounds were then subjected to further refinement using AM1 semiempirical quantum mechanics in Gaussian '09. The five kinases were all screened with a set of known HSP90 inhibitors, radicicol A and its derivatives. Functional group modifications were made to the radicicol compounds, and they were docked into the five kinases.