Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach

Abstract

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

Graphical Abstract

Keywords:

• Non-small cell lung cancer
• EGFR
• allosteric
• library generation
• virtual screening
• molecular docking
• molecular dynamics simulations

Acknowledgements

The authors are thankful to The Head, Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004 (MS), India, for providing the laboratory facility. The authors are also thankful to The Head, Department of Biotechnology, KLEF University, Vaddeswaram 522502 (AP), India for the computational support.

Disclosure statement

The authors declare no competing financial interest.

Funding

The authors K. S. K and P. S. W are thankful to Indian Council of Medical Research (ICMR) for providing funding in support of Senior Research Fellowship with Ref No: 3/2/2/33/2018/Online OncoFship/NCD-III. The author P. V. L. S. B is thankful to Indian Council of Medical Research (ICMR) [ISRM/12(07)/2019] and DST-SERB [CRG/2018/003276] for providing financial support.

Table 1. Comparison of docking score with relative binding free energy score along with interacting residues of top 50 hits.

Additional information

Funding

The authors K. S. K and P. S. W are thankful to Indian Council of Medical Research (ICMR) for providing funding in support of Senior Research Fellowship with Ref No: 3/2/2/33/2018/Online OncoFship/NCD-III. The author P. V. L. S. B is thankful to Indian Council of Medical Research (ICMR) [ISRM/12(07)/2019] and DST-SERB [CRG/2018/003276] for providing financial support.