Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach.
| Autor: | Karnik KS; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India., Sarkate AP; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India., Lokwani DK; R. C. Patel College of Pharmacy, R. C. Patel Institute of Pharmaceutical Education & Research, Shirpur, India., Narula IS; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India., Burra PVLS; Department of Biotechnology, KLEF University, Vaddeswaram, India., Wakte PS; Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, India. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2021 Sep; Vol. 39 (15), pp. 5376-5398. Date of Electronic Publication: 2020 Jul 01. |
| DOI: | 10.1080/07391102.2020.1786460 |
| Abstrakt: | The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance. Communicated by Ramaswamy H. Sarma. |
| Databáze: | MEDLINE |
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