Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3- d]pyrimidine derivatives as new EGFR inhibitors

Eman A Sobh; Mohammed A Dahab; Eslam B Elkaeed; Aisha A Alsfouk; Ibrahim M Ibrahim; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.1080/14756366.2023.2220579

Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3- d]pyrimidine derivatives as new EGFR inhibitors

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2220579. doi: 10.1080/14756366.2023.2220579.

Authors

Eman A Sobh¹, Mohammed A Dahab², Eslam B Elkaeed³, Aisha A Alsfouk⁴, Ibrahim M Ibrahim⁵, Ahmed M Metwaly^{6

7}, Ibrahim H Eissa²

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
³ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
⁵ Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt.
⁶ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁷ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.

Abstract

A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFR^WT and EGFR^T790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFR^WT and EGFR^T790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

Keywords: Anti-proliferative; EGFR inhibitors; MD simulations; apoptosis; thieno[2,3-d]pyrimidines.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors* / antagonists & inhibitors
Humans
Lung Neoplasms*
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemistry
Pyrimidines / chemistry
Structure-Activity Relationship
bcl-2-Associated X Protein

Substances

Antineoplastic Agents
bcl-2-Associated X Protein
EGFR protein, human
ErbB Receptors
Protein Kinase Inhibitors
Pyrimidines

Grants and funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R116), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work.