Computational virtual screening and structure-based design of some epidermal growth factor receptor inhibitors

Muhammad Tukur Ibrahim,Gideon Adamu Shallangwa,Adamu Uzairu,Sani Uba

doi:10.1186/s43094-020-00074-6

Muhammad Tukur Ibrahim, Gideon Adamu Shallangwa + Show 2 more

Open Access

https://doi.org/10.1186/s43094-020-00074-6

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Abstract

BackgroundThe foremost cause of cancer mortality worldwide was lung cancer. Lung cancer is divided into small cell lung cancer and non-small cell lung cancer (NSCLC). The latter is the main type of lung cancer that account for about 90% of the cancer issues and estimate about 25% of the cancer mortality each year in the world. Among the types of lung cancer with about 1.5 million patients and less than 20% survival rate is NSCLC. Overexpression of EGFR tyrosine kinase was recognized to be the cause of NSCLC. Therefore, there is a need to develop more EGFR inhibitors due to drug-resistance development by the mutation.ResultComputational virtual screening on some epidermal growth factor receptor inhibitors (EGFRL858R/T790M inhibitors or NSCLC therapeutic agents) against their target protein (EGFR tyrosine kinase receptor pdb entry 3IKA) was performed via molecular docking simulation and pharmacokinetics to identify hit compounds with a promising affinity toward their target. The hit compounds discovered were compound 22 with −9.8 kcal/mol, 24 with −9.7 kcal/mol, 17 with −9.7 kcal/mol, and 19 with −9.5 kcal/mol respectively. These lead compounds were further subjected to drug-likeness and ADME prediction and found to be orally bioavailable. Six (6) new EGFRL858R/T790M inhibitors using compound 22 with the highest binding affinity as a template were designed.ConclusionThe six newly EGFRL858R/T790M inhibitors were found to have a better binding affinity than the template used in the designing process and AZD9291 (the positive control). None of the designed compounds was found to violate more than the permissible limit set by RO5 thereby predicting their easy transportation, absorption, and diffusion. More so, the designed compounds were found to have good synthetic accessibility which indicates that these designed compounds can be easily synthesized in the laboratory.

Highlights

The foremost cause of cancer mortality worldwide was lung cancer
This work is aimed at carrying out computational virtual screening on some EGFRL858R/T790M inhibitors using molecular docking to identify hit compounds with a promising affinity against their target receptor (EGFR tyrosine kinase receptor), confirm their bioavailability via their pharmacokinetics and drug-likeness properties, and design new potent EGFRL858R/T790M inhibitors that have better binding affinity than the template
Molecular docking simulation The results of the molecular docking simulation are presented in Table 2 and Figs. 3 and 4 respectively

Summary

Introduction

Lung cancer is divided into small cell lung cancer and non-small cell lung cancer (NSCLC) The latter is the main type of lung cancer that account for about 90% of the cancer issues and estimate about 25% of the cancer mortality each year in the world. Overexpression of EGFR tyrosine kinase was recognized to be the cause of NSCLC. Result: Computational virtual screening on some epidermal growth factor receptor inhibitors (EGFRL858R/T790M inhibitors or NSCLC therapeutic agents) against their target protein (EGFR tyrosine kinase receptor pdb entry 3IKA) was performed via molecular docking simulation and pharmacokinetics to identify hit compounds with a promising affinity toward their target. The hit compounds discovered were compound 22 with −9.8 kcal/mol, 24 with −9.7 kcal/mol, 17 with −9.7 kcal/mol, and 19 with −9.5 kcal/mol respectively These lead compounds were further subjected to drug-likeness and ADME prediction and found to be orally bioavailable. The treatment of EGFR tyrosine kinase to managed NSCLCs became a very urgent therapeutic necessity [3]

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