title: Identification and Pharmacological Analysis of High Efficacy Small Molecule Inhibitors of EGF-EGFR Interactions in Clinical Treatment of Non-Small Cell Lung Carcinoma: a Computational Approach.
abstract: Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN-PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound- AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC-0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches.
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad, India E-mail : anuraj@eminentbio.com.
authors.forename: Suresh
authors.initials: S
authors.lastname: Gudala
authors.forename: Uzma
authors.initials: U
authors.lastname: Khan
authors.forename: Niteesh
authors.initials: N
authors.lastname: Kanungo
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Tajamul
authors.initials: T
authors.lastname: Hussain
authors.forename: Ms
authors.initials: M
authors.lastname: Parihar
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.forename: Hema Prasad
authors.initials: HP
authors.lastname: Mundluru
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors