3D structure prediction of VAPC1 and identification of dual natural inhibitors for VPAC1 and EGFR.

ABSTRACT

Vasoactive intestinal polypeptide receptor 1 (VPAC1) and epidermal growth factor receptor (EGFR) are associated with signal transduction pathways relevant to neuroblastoma, cancer of breast, prostate and lungs. In order to identify appropriate ligand analogues for simultaneous inhibition of EGFR and VPAC1, in-silico homology modelling of VPAC1 and its characterization by molecular interaction studies have been undertaken. Homology modelling was performed with the Swiss Model and validation of the predicted 3D structure was carried out using PROCHECK and RAMPAGE. Ramachandran's plot of the predicted structure from this two software revealed that 92% and 94% of the residues were in the most favoured region, respectively. Compounds screened from Naturally Occurring Plant-based Anti-Cancerous Compound-Activity-Target (NPACT) database having strong interactions with EGFR were further checked for ADMET properties. Molecular interaction studies revealed four compounds namely Fisetin, Genistein, Tectorigenin, and Tephrosin docked with VPAC1 having respective binding energies of -7.1, -6.98, -6.9 and - 6.61 kcal/mol. Fisetin and Genistein with a rotatable bond and lower molecular weight increased their drug-likeness than the others. Therefore, simultaneous inhibition of VPAC1 and EGFR, in turn, might inhibit the progression of breast carcinoma. The results obtained were further substantiated by comparing them with positive and negative controls. Quercetin was used as positive control, and strong binding energy of -7.54 kcal/mol with EGFR is in accordance with experimental evidence. 3-O-cis-p coumaroyl alphitolic acid was used as negative control, where docking was not possible in absence of binding with either EGFR or VIPR1.