In silico exploration of Qur’anic-based natural products as potential anticancer BRAF inhibitors via structure-based virtual screening
TL;DR
This study aimed to identify novel BRAF V600E inhibitors through an in silico evaluation of the binding affinity and ADMET safety profile of bioactive compounds from 32 Qurʼanic natural product plants, utilizing a structure-based virtual screening of 2,308 compounds.
Abstract
The BRAF V600E mutation, namely the substitution of valine (non-polar/hydrophobic) with Glutamic Acid (polar/negative) at position 600, mimics biological phosphorylation and stabilizes the kinase in a permanently active conformation (constitutive activation) promoting uncontrolled melanoma cell proliferation. First-generation synthetic inhibitors, such as vemurafenib and dabrafenib, face challenges of clinical resistance owing to protein dimerization. This study aimed to identify novel BRAF V600E inhibitors through an in silico evaluation of the binding affinity and ADMET safety profile of bioactive compounds from 32 Qurʼanic natural product plants, utilizing a structure-based virtual screening of 2,308 compounds (2,301 valid compounds after structural filtration). The target (PDB: 3OG7, empirical crystallography resolution 2.45 Å; R-free: 0.258; R-work: 0.212) was used as the receptor. Molecular docking was performed using AutoDock 4.2 with the Lamarckian Genetic Algorithm (LGA). Validation was carried out through 100 redocking replications with a median RMSD value of 0.377 Å (range 0.31–0.43 Å), well below the validity threshold of 2.0 Å. A total of 1,310 compounds (56.9%) meet the SBVS criteria based on interactions at the Cys532 and Asp594 hotspot residues. The three best candidates from ginger (Zingiber officinale): (1) Diarylheptanoid Ketone Derivative (-11.37 kcal/mol), (2) Glycosylated Gingerol Derivative (-10.58 kcal/mol), and (3) Hexahydrocurcumin Analog (-10.57 kcal/mol), show the highest binding affinity and met Lipinski’s Ro5. Ginger derivatives represent promising lead compounds targeting type IIB kinases, with binding energies reaching -11 kcal/mol. However, prior to clinical trials, molecular optimization is recommended to mitigate the risk of cardiotoxicity (hERG, probability 0.635 in compound 3) and hepatotoxicity (DILI, probability 0.364 in compound 2).