Virtual Screening to Identify Novel Inhibitors of Pan ERBB Family of Proteins from Natural Products with Known Anti-tumorigenic Properties

Abstract

Overexpression of ERBBB family of receptors (ERBB1, ERBB2, ERBB3 and ERBB4) has been found to be hyper-activated in a number of different types of cancers. Here we studied 20 molecules through molecular docking studies to find out a natural product that can inhibit signaling through them and exert anti-tumor activity as a result. Natural products were selected from various natural products databases and also from previous studies on natural products with anti-tumor properties and tyrosine kinase inhibitors in general. Molecular docking, physiochemical and Absorption, Distribution, Metabolism and Excretion (ADME) analysis, interaction analysis, molecular dynamics (MD) simulations and free energy calculations were performed. The molecular docking results revealed that diplacone, diplacol, quercetin, genistin and resveratrol show promise in inhibiting ERBB family of proteins. ADME analysis predict diplacone and diplacol to have acceptable pharmacokinetic properties. Interaction analysis revealed that the hydrophobic surface regions and charged amino acids such as Lys an Asp are important for proper interactions of inhibitors with ERBB proteins. MD study and free energy calculation showed that diplacone binds with ERBB proteins as a stable complex and has significantly higher binding affinity. Diplacone can be considered as a potent pan-ERBB inhibitors for treatment of various types of cancers.