How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study

Abstract

Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.

EGFR degraders in non‐small‐cell lung cancer: Breakthrough and unresolved issue

“…There are seven α‐helices and seven β‐sheets in the intracellular domain, and the inhibitor can be firmly locked in the “mouth‐like” structure and compete with the natural substrate for the ATP‐binding site. The groove in the “mouth” consists of five functional regions, which are the P‐loop (Ser720 to Gly724), α‐loop (Arg748 to Ser752), Cα‐helix (Pro753 to Ser768), hinge‐region (Gln791 to Leu798), and DFG motif (Thr854 to Arg858) (Liu et al., 2020).…”

Mechanism Exploration of Amyloid-β-42 Disaggregation by Single-Chain Variable Fragments of Alzheimer’s Disease Therapeutic Antibodies

“…First, the energies of the complex systems were relaxed with steepest-descent energy minimization to eliminate steric clashes or incorrect geometry. After that, 100 ps NVT (constant Number of particles, Volume, and Temperature) and NPT (constant Number of particles, Pressure, and Temperature) were alternately operated with position restraints on scFv-C and Aβ 5 to relax the solvent molecules in two phases [44,45]. The solvent molecules were equilibrated with a fixed protein at 310 K, and the initial velocities were chosen from a Maxwellian distribution.…”