Virtual Screening to Identify Novel Inhibitors of Pan ERBB Family of Proteins from Natural Products with Known Anti-tumo
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Virtual Screening to Identify Novel Inhibitors of Pan ERBB Family of Proteins from Natural Products with Known Anti‑tumorigenic Properties Ishtiaque Ahammad1 · Md. Rafiul Islam Sarker1 · Akib Mahmud Khan2 · Sohidul Islam1 · Mahmud Hossain2 Accepted: 5 December 2019 © Springer Nature B.V. 2019
Abstract Overexpression of ERBBB family of receptors (ERBB1, ERBB2, ERBB3 and ERBB4) has been found to be hyper-activated in a number of different types of cancers. Here we studied 20 molecules through molecular docking studies to find out a natural product that can inhibit signaling through them and exert anti-tumor activity as a result. Natural products were selected from various natural products databases and also from previous studies on natural products with anti-tumor properties and tyrosine kinase inhibitors in general. Molecular docking, physiochemical and Absorption, Distribution, Metabolism and Excretion (ADME) analysis, interaction analysis, molecular dynamics (MD) simulations and free energy calculations were performed. The molecular docking results revealed that diplacone, diplacol, quercetin, genistin and resveratrol show promise in inhibiting ERBB family of proteins. ADME analysis predict diplacone and diplacol to have acceptable pharmacokinetic properties. Interaction analysis revealed that the hydrophobic surface regions and charged amino acids such as Lys an Asp are important for proper interactions of inhibitors with ERBB proteins. MD study and free energy calculation showed that diplacone binds with ERBB proteins as a stable complex and has significantly higher binding affinity. Diplacone can be considered as a potent pan-ERBB inhibitors for treatment of various types of cancers. Keywords ERBB · HER · Molecular docking · Natural product · Diplacone
Introduction The ERBB family of proteins (ERBB1, ERBB2, ERBB3 and ERBB4) has been targeted for treating breast, lung, stomach, and various other carcinomas (Bublil and Yarden 2007; Roskoski 2014a). Various small molecule protein kinase inhibitors, monoclonal antibodies and combination of monoclonal antibodies and tyrosine kinase inhibitors are being used to treat various types of cancers (Roskoski 2014b). ERBB2 overexpression has been found to result in Ishtiaque Ahammad, Md. Rafiul Islam Sarker, and Akib Mahmud Khan have contributed equally. * Mahmud Hossain [email protected] 1
Department of Biochemistry and Microbiology, North South University, Dhaka, Bangladesh
Laboratory of Neuroscience and Neurogenetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka 1000, Bangladesh
2
increased cancer metastasis (Wang 2010). Overexpression of ERBB3 had a significant negative prognostic effect on disease-specific survival (Chiu et al. 2010). ERBB4 has been found to be over-expressed in colorectal cancer and non-small cell lung cancer (Williams et al. 2015; Deng et al. 2008). Due to their role in tumorigenesis, ERBB family of receptors make attractive therapeutic targets in various cancers (Fuller et al. 2008). Tumors involving
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