Natural alkaloids targeting EGFR in non-small cell lung cancer: Molecular docking and ADMET predictions

• Published in: Chemico-biological interactions Vol. 358; p. 109901
• Main Authors: Saini, Nidhi, Grewal, Ajmer Singh, Lather, Viney, Gahlawat, Suresh Kumar
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.05.2022
• Subjects: Alkaloids; Alkaloids - chemistry; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Epidermal growth factor receptor; ErbB Receptors - metabolism; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Humans; Lung Neoplasms - drug therapy; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein kinases; Tyrosine kinase inhibitor; Alkaloids; Tyrosine kinase inhibitor; Protein kinases; Epidermal growth factor receptor; Cancer
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2022.109901

The phytochemicals contribute to the processes of protection and interaction by acting as antioxidants, anti-mutagens, anticarcinogens, and antimicrobial agents. Among the diverse families of phytoconstituents, alkaloids play an essential role in medicine. These are low-molecular-mass compounds containing nitrogen and are generally alkaline. In this study, in silico molecular docking was performed using AutoDock Vina for thirty-one alkaloids against epidermal growth factor receptor (EGFR). Erlotinib was used as a reference ligand for this study. Erlotinib has been linked to various serious side effects over the past decade, including folliculitis, diarrhoea, paronychia, fatigue, conjunctivitis, ectopion, and epiphora of the lower eyelids. This study found sanguinarine (−10.7 kcal mol−1) to be the most potent inhibitor of EGFR as compared to erlotinib (−7.5 kcal mol−1). Other alkaloids namely, isocolumbin (−9.3 kcal mol−1), lunamarine (−9.1 kcal mol−1), ajmaline (−8.6 kcal mol−1), magnoflorine (−8.6 kcal mol−1) and jatrorrhizine (−8.5 kcal mol−1) also showed potent inhibition against EGFR, but the stability of these molecules with EGFR was less than sanguinarine and more than erlotinib. These were stable and ideal pharmaceutical alkaloids because of their significant interactions, minimal Gibbs free energy, safety, effectiveness and selectivity. Amongst the 31 alkaloids subjected to ADMET prediction, 29 alkaloids followed Lipinski's rule of five. These 29 alkaloids were predicted to have high bioavailability, high lead-likeness score, low toxicity and were easier to synthesize. Compared to erlotinib, other molecules showed less or no inhibition of EGFR. The six named compounds listed above may be potent inhibitors for EGFR mutated cancers, as for example non-small cell lung cancer, colorectal cancer, and pancreatic cancer. [Display omitted] •Sanguinarine displayed the highest inhibition of EGFR when compared with erlotinib.•Binding with EGFR involved H-bonding and hydrophobic interactions.•Ajmaline, magnoflorine, isocolumbin, lunamarine, jatrorrhizine also inhibited EGFR.•Based on Lipinski's rule of 5, almost all molecules exhibited drug-like properties.