Targeting EGFR allosteric site with marine-natural products of Clathria Sp.: A computational approach

Abstract

The EGFR-C797S resistance mutation to third-generation drugs has been overcome by fourth-generation inhibitors, allosteric inhibitors, namely EAI045 and has reached phase 3 clinical trials, so the Allosteric Site is currently an attractive target for development. In this study, researchers are interested in knowing the activity of metabolite compounds from marine natural ingredients Clathria Sp. against the Allosteric Site of EGFR computationally. The methods used include molecular docking using Autodock4 software and Molecular Dynamics simulation performed using GROMACS software. The research began with the preparation of metabolite samples from Clathria Sp. through the KnapSack database site and the preparation of EGFR receptors that have been complexed with allosteric inhibitors, namely proteins with PDB code 5D41. Each compound was docked to the Allosteric Site of the natural ligand and then molecular dynamics simulations were performed on the compound with the best docking energy compared to the natural ligand. From the docking results, the Clathrin_A compound showed the lowest binding energy compared to other metabolites, and the value was close to the natural ligand. Then from the molecular dynamics results, the clathrin_A compound shows good stability and resembles the natural ligand, which is analyzed through RMSD, RMSF, SASA, Rg, and PCA, and shows the binding free energy from MMPBSA analysis which is close to the natural ligand. It can be concluded, Clathrin_A compound has potential as an allosteric inhibitor.