In-Silico Screening Of Phytochemicals For Anaplastic Lymphoma Kinase Positive Oncogenicity

Abstract

Anaplastic Lymphoma Kinase (ALK) receptor inhibitors have been in use to treat ALK positive oncogenic situations like Non Small Cell Lung Cancer (NSCLC) from last two decades but issues like Acquired Drug resistance (ADR) and lipophilicity associated poor penetrations always created a lacuna for these inhibitors to become a successful therapy. Despite the availability of three generations of FDA approved ALKIs at present we seek a need to identify few noval ALKIs among phytochemicals which are deemed to be less toxic and safer with better body penetrations. Current in-silico screening facilitated by Maestro 13.1 modeling interface by Schrodinger, LLC was conducted to screen a pool of about 1500 phytochemicals from 24 chemical classes such as Aloins, Limonoids, Curcumins, Benzimidazoles etc. The virtual protein 8ARJ, downloaded from Protein Data Bank was conditioned to generate receptor grid of ALK followed by creating pool of preconditioned phytochemical ligands having structures in view to contain certain cellular receptor based therapeutic activity along with structural similarities with binding cavity of receptor. Standard ALK inhibitors like Entrectinib, Alectinib etc were also evaluated as reference. This in silico study process includes an initial ADMET prescreening by QikPro wizard followed by docking an initial HTVS followed by standard precision and at last by extra precision mode. At last it can be concluded that; Curcumins phytochemicals must be researched & developed as a new generation of noval ALK inhibitors supported by fact that 10 out of top 18 phytochemicals belongs only to Curcumin family. Secondly phytochemicals identified as ALK inhibitors are Indirubin (Benzimidazole, Pubchem ID10177), Xanthoangelol (Limonoids, Pubchem ID 85134973) and Curcumin (Pubchem ID 442783), with their docking scores of -9.324, -9.254 and -9.025 respectively as compared to docking scores of standard ALK inhibitors like Entrectinib, Crizotinib and Brigatinib having docking scores of -9.361, -8.224 and -8.111 respectively.