Structural investigations of T854A mutation in EGFR and identification of novel inhibitors using structure activity relationships

Abstract

BackgroundThe epidermal growth factor receptor (EGFR) is a member of the ErbB family that is involved in a number of processes responsible for cancer development and progression such as angiogenesis, apoptosis, cell proliferation and metastatic spread. Malfunction in activation of protein tyrosine kinases has been shown to result in uncontrolled cell growth. The EGFR TK domain has been identified as suitable target in cancer therapy and tyrosine kinase inhibitors such as erlotinib have been used for treatment of cancer. Mutations in the region of the EGFR gene encoding the tyrosine kinase (TK) domain causes altered responses to EGFR TK inhibitors (TKI). In this paper we perform molecular dynamics simulations and PCA analysis on wild-type and mutant (T854A) structures to gain insight into the structural changes observed in the target protein upon mutation. We also report two novel inhibitors identified by combined approach of QSAR model development.ResultsThe wild-type and mutant structure was observed to be stable for 26 ns and 24 ns respectively. In PCA analysis, the mutant structure proved to be more flexible than wild-type. We developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds which was later used for prediction of inhibitory activity of natural compounds of ZINC library. The 3D-QSAR model was proved to be robust by the statistical parameters such as r2 (0.9751), q2(0.9491) and pred_r2(0.9525).ConclusionAnalysis of molecular dynamics simulations results indicate stability loss and increased flexibility in the mutant structure. This flexibility results in structural changes which render the mutant protein drug resistant against erlotinib. We report two novel compounds having high predicted inhibitory activity to EGFR TK domain with both wild-type and mutant structure.

Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs

“…Since the structures obtained were homomer complex structures, only the monomer chain was selected and rest including water and non-bonded atoms were removed using Accelyrs Viewer lite 5.0 [2, 15, 19]. The combinatorial library compounds with good predicted activity were selected and prepared using Ligprep and protein structure was prepared using Protein Preparation wizard [24–27].…”

“…In this study we developed a novel GQSAR model based on congeneric series of acylguanidine zanamivir derivatives [17–19]. Same set of congeneric series were counter screened against NA of both H1N1 and H3N2.…”

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

“…For many proteins implicated in cancer, structural biology information has proven invaluable for understanding their functional implications as well as discovering novel therapeutic modalities. [49][50][51][52] Unfortunately, it is difficult to study mucins structurally by traditional methods. Crystallographic methods falter because of the sheer size of mucins (up to 14 000 kDa), extensive variation in the number of tandem repeats within the VNTR (up to 120), sequence variation, and inability to clone, express, and purify fully folded and glycosylated forms.…”

“…For many proteins implicated in cancer, structural biology information has proven invaluable for understanding their functional implications as well as discovering novel therapeutic modalities . Unfortunately, it is difficult to study mucins structurally by traditional methods.…”

A computational method for the identification of candidate drugs for non-small cell lung cancer

“…Goyal et al . developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds against EGFR, which is a target associated with NSCLC, and obtained two novel inhibitors by screening ZINC libraries [ 5 ]. Xiang et al .…”