Structure-based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Metabolic Reactivity Studies of Quinazoline Derivatives for their Anti-EGFR Activity Against Tumor Angiogenesis

Abstract

The development and progression of tumour cells are solely and utterly dependent on the phenomenon of angiogenesis to furnish the necessary supply of oxygen and nutrients and waste removal mechanisms to tumour cells. The phenomenon of tumour angiogenesis itself results from the over-expression of various receptor tyrosine kinases like EGFR, VEGFR, PDGFR, FGFR, etc. EGFR tyrosine kinase is involved in the growth, development, proliferation, and metastasis of various cancers, including ovarian cancer, NSCLC, head and neck cancer, brain cancer and breast cancer. There are different tumour angiogenic pathways associated with the expression of EGFR tyrosine kinase, including the RAS-RAF-MEK-ERK-MAPK pathway, PI3K-AKT pathway and PLC-Ƴ –PKC pathway that result in the growth, proliferation, progression, and metastasis of tumour cells. To date, tremendous research has focussed on the development of safe therapeutic strategies against tumors but the acquired mutational resistance to existing drugs, persistent drug side effects, and low efficacy with therapeutic longevity of drugs compels us to identify novel potential anti-EGFR leads with good efficacy and minimal side effects. In this study, we aimed at developing and designing novel quinazoline based derivatives as an EGFR antagonist to inhibit tumor angiogenesis phenomenon. With the aid of in silico structure-based virtual screening, molecular docking, and MD simulation approaches, we identified the top three leads viz. QU524 (CID:46916170), QU571 (CID:44968219) and QU297 (CID:70702306) as the potential anti-EGFR compounds possessing higher binding energy of -8.64 kcal/mol, -8.24 kcal/mol -8.10 kcal/mol, respectively compared to control drug, erlotinib with binding energy of -7.72 kcal/mol. The above selected leads also cleared ADME, toxicity, metabolic reactivity and cardiotoxicity profile filters. Based on the good binding affinity, pharmacokinetic profiling and stability of the bound complexes we propose the selected leads as prominent EGFR inhibitors to halt the phenomenon of tumor angiogenesis.

Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers

“…For patients with esophageal squamous cell carcinoma who cannot tolerate chemoradiotherapy, the administration of erlotinib combined with radiotherapy was more tolerable and effective ( Zhai et al, 2013 ). The targeted search for improved inhibition of angiogenesis continues and resulted in the design of more efficient inhibitors of EGFR signaling ( Shah et al, 2023 ), although clinical testing is required before those drugs can be implemented. Conclusively, the previous studies showed that local control rate and overall survival rate of patients who were treated with angiogenesis inhibitor combined with radiotherapy are significantly improved compared with radiotherapy alone.…”

Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor

“…To effectively combat breast cancer, a multitargeted drug design approach is envisaged. This strategy involves the development of a single drug, capable of simultaneously targeting multiple proteins or pathways associated with breast cancer [ 17 , 18 , 19 , 20 ]. Such a drug would inhibit the oestrogen receptor signalling pathway (1M17), disrupt the overexpression of HER2 (3RCD), introduce vulnerabilities in DNA repair mechanisms (5NWH), and modulate the interactions or functions of proteins regulating BRCA1 (4KD7) [ 13 , 14 , 15 , 16 ].…”

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

“…Tumour cells can adapt and evolve, rendering these drugs ineffective over time. This adaptability is a significant obstacle in lung cancer treatment and highlights the need for more comprehensive therapeutic approaches [ 16 , 17 , 18 , 19 , 20 ].…”