Modern Chemistry & Applications

A quantum mechanical AMBER compatible algebraic in silico discovery of the Microcrylaq multiepitope mimic poly pharmacophore targeted to the G719S/T790M double mutant for the regulation of drug sensitivities caused by di

Joint Event on 19^th International Conference on Medicinal Chemistry & Multi Targeted Drug Delivery & International Conference on Catalysis and Pyrolysis

November 05-06, 2018 | San Francisco, USA

Ioannis Grigoriadis

Biogenea Pharmaceuticals Ltd., Greece

Keynote: Mod Chem Appl

Abstract:

The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. Latest biochemical analyses have been revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. Different patterns for substrate docking are also studied depending on the choice of G719S/T790M double mutant model and state. Newly parameterized G719S/T790M double mutant models are tested in implicit and explicitly solvated MD simulations in the absence and presence of MicrocrylaqTM chemical structures and appear to be stable on the nanosecond simulation timescale. Taken together, our results provide a structural basis for the altered drug sensitivities caused by utilizing our quantum mechanical AMBER compatible algebraic computing approach for structural proteome-wide ligand-binding site comparisons of the MicrocrylaqTM multi-epitope mimic poly-pharmacophore targeted to the G719S/T790M double mutant for the regulation of drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

Biography :

Ioannis Grigoriadis has completed his PharmacistD at the age of 24 years from Aristotle University of Thessaloniki. He is the scientific director of Biogenea Pharmaceuticals Ltd., a premier biotechnology personalized cancer vaccination service organization. He has published more than 200 papers in reputed drug designing journals.

E-mail: jgrigoriadis@biogenea.gr