Virtual Screening of Hamigomycin B Natural Product Derivatives in 26 Kinase Proteins

Abstract

Hamigeromycin B and its analogs are synthetic natural product derivatives that may be useful at mediating signal transduction activity in human kinases. To study this potential activity, 11 Hamigomycin analogs were constructed using MOE 2019 and subjected to energy minimization using the AMBER14:EHT force field. Each analog was also compared against the parameters of Lipinski’s Rules of Five to determine druggability. The compounds were docked into twenty-six human kinase structures obtained from the Protein Data Bank (www.rcsb.org) to obtain relative binding free energy scores using the Docking module of MOE 2019. The binding sites for these kinase proteins were analyzed using the Evolutionary Trace server (http://lichtargelab.org/software/ETserver; Lichtarge Laboratory; Baylor University; Houston, TX USA) and the Protein Frustratometer (http://frustratometer.qb.fcen.uba.ar/; EMBNet Argentina; Buenos Aires, Argentina) to characterize the energetics and evolutionary information of the amino acid residues for likely contributions to binding. The lowest docking scores were used to determine the best binding and orientation of each analog to each protein. Docking data suggest good binding of these analogs with five out of twenty-six human kinase proteins. Functional group modifications were done to the original compounds in an effort to enhance binding to these five kinases. Future in vitro studies are being planned to confirm the computational docking results. Preliminary computational results will be disseminated.