2. Academic Validation
  3. Computer aided drug discovery (CADD) of a thieno[2,3- d]pyrimidine derivative as a new EGFR inhibitor targeting the ribose pocket

Computer aided drug discovery (CADD) of a thieno[2,3- d]pyrimidine derivative as a new EGFR inhibitor targeting the ribose pocket

  • J Biomol Struct Dyn. 2024 Mar;42(5):2369-2391. doi: 10.1080/07391102.2023.2204500.
Eman A Sobh 1,  Mohammed A Dahab 2,  Eslam B Elkaeed 3,  Aisha A Alsfouk 4,  Ibrahim M Ibrahim 5,  Ahmed M Metwaly 6 7,  Ibrahim H Eissa 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Shibin-Elkom, 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.
PMID: 37129193 DOI: 10.1080/07391102.2023.2204500
Abstract

Depending on the pharmacophoric characteristics of EGFR inhibitors, a new thieno[2,3-d]pyrimidine derivative has been developed. Firstly, the potential inhibitory effect of the designed compound against EGFR has been proven by docking experiments that showed correct binding modes and excellent binding energies of -98.44 and -88.00 kcal/mol, against EGFR wild-type and mutant type, respectively. Furthermore, MD simulations studies confirmed the precise energetic, conformational, and dynamic alterations that occurred after binding to EGFR. The correct binding was also confirmed by essential dynamics studies. To further investigate the general drug-like properties of the developed candidate, in silico ADME and toxicity studies have also been carried out. The thieno[2,3-d]pyrimidine derivative was synthesized following the earlier promising findings. Fascinatingly, the synthesized compound (4) showed promising inhibitory effects against EGFRWT and EGFRT790M with IC50 values of 25.8 and 182.3 nM, respectively. Also, it exhibited Anticancer potentialities against A549 and MCF-7cell lines with IC50 values of 13.06 and 20.13 µM, respectively. Interestingly, these strong activities were combined with selectivity indices of 2.8 and 1.8 against the two Cancer cell lines, respectively. Further investigations indicated the ability of compound 4 to arrest the Cancer cells' growth at the G2/M phase and to increase early and late Apoptosis percentages from 2.52% and 2.80 to 17.99% and 16.72%, respectively. Additionally, it was observed that compound 4 markedly increased the levels of Caspase-3 and caspase-9 by 4 and 3-fold compared to the control cells. Moreover, it up-regulated the level of Bax by 3-fold and down-regulated the level of Bcl-2 by 3-fold affording a Bax/Bcl-2 ratio of 9.Communicated by Ramaswamy H. Sarma.

Keywords

3-d]pyrimidine; CADD; EGFR inhibitors; MD simulations; apoptosis; docking; thieno[2.

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