Molecular design of anticancer drugs from marine fungi derivatives

Abstract

Heat shock protein 90 (Hsp90) is one of the most potential targets in cancer therapy. We have demonstrated using a combination of molecular docking and fast pulling of ligand (FPL) simulations that marine fungi derivatives can be possible inhibitors, preventing the biological activity of Hsp90. The computational approaches were validated and compared with previous experiments. Based on the benchmark of available inhibitors of Hsp90, the GOLD docking package using the ChemPLP scoring function was found to be superior over both Autodock Vina and Autodock4 in the preliminary estimation of the ligand-binding affinity and binding pose with the Pearson correlation, R = -0.62. Moreover, FPL calculations were also indicated as a suitable approach to refine docking simulations with a correlation coefficient with the experimental data of R = -0.81. Therefore, the binding affinity of marine fungi derivatives to Hsp90 was evaluated. Docking and FPL calculations suggest that five compounds including 23, 40, 46, 48, and 52 are highly potent inhibitors for Hsp90. The obtained results enhance cancer therapy research.

Fig. 1. Computational modelling of molecular docking and FPL simulations.

Fig. 2. Association between the ChemPLP score and the experimental binding free energy ΔG_EXP.

Fig. 3. Association between the average of the F_Max and the experimental binding free energy ΔG_EXP.

Fig. 4. The 6 binding positions of the marine fungi compounds docking the best to Hsp90, which were estimated using the GOLD docking program with ChemPLP scoring function.