Sains Malaysiana 52(4)(2023): 1203-1215

http://doi.org/10.17576/jsm-2023-5204-13

Molecular Docking Analysis on the Designed Benzimidazole Derivatives as EGFR Inhibitors: Comparison between EGFR Wild-Type (EGFR_WT) and T790M Mutant

(Analisis Dok Molekul pada Terbitan Benzimidazol Direka sebagai Perencat EGFR: Perbandingan antara Jenis Liar EGFR (EGFRWT) dan Mutan T790M)

NURUL AWANI SYAZZIRA JALIL¹ & SHAFIDA ABD HAMID^1,2,*

¹Department of Chemistry, Kulliyyah of Science, International Islamic University Malaysia, 25200 Bandar Indera Mahkota, Kuantan, Pahang Darul Makmur, Malaysia

²SYNTOF, Kulliyyah of Science, International Islamic University Malaysia, 25200 Bandar Indera Mahkota, Kuantan, Pahang Darul Makmur, Malaysia

Diserahkan: 15 Ogos 2022/Diterima: 26 Februari 2023

Abstract

The non-small cell lung (NSCL) and colorectal cancers are frequently linked with the oncogenic activation of the epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family. Current tyrosine kinase inhibitors (TKIs) are susceptible to drug resistance mutations and induce cytotoxicity effects on normal EGFRs. The isosteric nature of benzimidazole with purine renders its great potential to imitate the binding mode of the purine-based ATP and prevents its contact with the EGFR active sites. Here, we report the molecular docking of 50 designed benzimidazole derivatives, as well as Gefitinib and ATP, to analyse and compare their binding modes at EGFR_wt and T790M active sites. The design of the ligands is based on our previous study, in which we proposed to evaluate keto- and amino-benzimidazoles, attached to a double bond linker and a phenyl group having electron donating and electron withdrawing groups attached at various positions. Docking simulations showed that keto-benzimidazoles dominated the top ten highest binding affinities in both EGFR-ligand complexes. The presence of sulfonyl substituents contributed to more stable complexes compared to others with binding energies of -8.1 (7c) and -7.8 (11c) kcal/mol in EGFR_wt, and -8.3 (7d) and -8.4 (1c) kcal/mol for T790M mutant. The substituent effects on the benzimidazole contributed not only to the hydrogen bonding and hydrophobic interaction, but also to the often-disregarded Van der Waals forces that are responsible for shape complementarity of the benzimidazoles with the EGFR binding pocket.

Keywords: Benzimidazole; EGFR; molecular docking; tyrosine kinase inhibitor; T790M

Abstrak

Sel paru-paru bukan kecil (NSCL) dan kanser kolorektum sering dikaitkan dengan pengaktifan onkogenik reseptor faktor pertumbuhan epidermis (EGFR), ahli keluarga reseptor tirosin kinase (RTK). Perencat tirosin kinase (TKI) masa kini terdedah kepada mutasi rintangan dadah dan mendorong kesan kesitotoksikan pada EGFR normal. Sifat isosterik benzimidazol dengan purin menyebabkan ia berpotensitinggi untuk meniru mod pengikatan ATP berasaskan purin dan menghalang sentuhannya dengan tapak aktif EGFR. Di sini, kami melaporkan dok molekul bagi 50 terbitan benzimidazol yang direka berserta Gefitinib dan ATP untuk menganalisis dan membandingkan mod pengikatan mereka di tapak aktif EGFRwt dan T790M. Reka bentuk ligan adalah berdasarkan kajian terdahulu kami dan kami mencadangkan untuk menilai benzimidazol-keto dan amino- yang terikat pada penghubung ikatan berganda dan kumpulan fenil yang mempunyai kumpulan pendermaan elektron dan penarikan elektron yang dilampirkan pada pelbagai kedudukan. Simulasi dok mendedahkan bahawa benzimidazol-keto menguasai sepuluh pertalian pengikatan tertinggi dalam kedua-dua kompleks ligan EGFR. Kehadiran penukarganti sulfonil menyumbang kompleks yang lebih stabil berbanding yang lain; dengan tenaga pengikatan -8.1 (7c) dan -7.8 (11c) kcal/mol dalam EGFRwt dan -8.3 (7d) dan -8.4 (1c) kcal/mol untuk mutan T790M. Kesan penukarganti pada benzimidazol menyumbang bukan sahaja kepada ikatan hidrogen dan interaksi hidrofobik, tetapi juga kepada daya Van der Waals yang sering diabaikan, yang bertanggungjawab untuk saling melengkapi bentuk benzimidazol dengan poket pengikat EGFR.

Kata kunci: Benzimidazol; dok molekul; EGFR; perencat tirosin kinase; T790M

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_*Pengarang untuk surat-menyurat; email: shafida@iium.edu.my