An insight into the mechanisms of action of selected bioactive compounds against epigenetic targets of prostate cancer: implications on histones modifications

Abstract

Prostate cancer is a leading cause of morbidity and mortality among men globally. In this study, we employed an in silico approach to predict the possible mechanisms of action of selected novel compounds reported against prostate cancer epigenetic targets and their derivatives, exhausting through ADMET profiling, drug-likeness, and molecular docking analyses. The selected compounds: sulforaphane, silibinin, 3, 3'-diindolylmethane (DIM), and genistein largely conformed to ADMET and drug-likeness rules including Lipinski's. Docking studies revealed strong binding energy of sulforaphane with HDAC6 (- 4.2 kcal/ mol), DIM versus HDAC2 (- 5.2 kcal/mol), genistein versus HDAC6 (- 4.1 kcal/mol), and silibinin against HDAC1 (- 7.0 kcal/mol) coupled with improved binding affinities and biochemical stabilities after derivatization. Findings from this study may provide insight into the potential epigenetic reprogramming mechanisms of these compounds against prostate cancer and could pave the way toward more success in prostate cancer phytotherapy.

Keywords: 3, 3’-diindolylmethane; Bioactive compounds; Epigenetics; Genistein; Prostate cancer; Silibinin; Sulforaphane.

Fig. 1

Structures of the selected compounds and their derivatives. A: Silibinin B: Silibinin (SL1) C: Silibinin (SL2) D: 3,3’-diindolylmethane E: 3,3’-diindolylmethane (D1) F: 3,3’-diindolylmethane (D2) G: Genistein H: Genistein (G1) I: Genistein (G2) J: Sulforaphane K: Sulforaphane (S1) L: Sulforaphane (S2)

Fig. 2

Venn diagram of the prostate cancer epigenetic targets (the light blue circles) and the selected compounds’ targets (the pink circles) (A) sulforaphane (B) silibinin (C) 3,3’-diindolylmethane (D) Genistein

Fig. 3

Prostate cancer epigenetic targets best associated with the selected compounds (A) sulforaphane (B) silibinin (C) 3,3’-diindolylmethane (D) Genistein

Fig. 4

Boiled egg representation of absorption and distribution properties of the selected compounds and their derivatives. S1 and S2 derivatives of sulforaphane, SL1 and SL2 derivatives of silibinin, D1 and D2 derivatives of 3,3’-diindolylmethane, and G1 and G2 derivatives of genistein. BBB blood-brain barrier, HIA human intestinal absorption, PGP P-glycoprotein

Fig. 5

3D Interaction of the Compounds with Target proteins. A sulforaphane with HDAC6, B silibinin with HDAC1, C 3,3’-diindolylmethane with HDAC2, D genistein with HDAC6

Fig. 6

2D Interaction of the compounds with target proteins. A sulforaphane with HDAC6, B silibinin with HDAC1, C 3,3’-diindolylmethane with HDAC2, D genistein with HDAC6