2. Academic Validation
  3. Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR

Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR

  • J Phys Chem B. 2024 Dec 19;128(50):12389-12402. doi: 10.1021/acs.jpcb.4c06246.
Duangjai Todsaporn 1,  Alexander Zubenko 2,  Victor G Kartsev 3,  Panupong Mahalapbutr 4,  Athina Geronikaki 5,  Samvel N Sirakanyan 6,  Lyudmila N Divaeva 7,  Victoria Chekrisheva 2,  Ilkay Yildiz 8,  Kiattawee Choowongkomon 9,  Thanyada Rungrotmongkol 1 10
Affiliations

Affiliations

  • 1 Center of Excellence in Biocatalyst and Sustainable Biotechnology, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
  • 2 North-Caucasian Zonal Research Veterinary Institute, 346406 Novocherkassk, Russia.
  • 3 InterBioScreen, 85355 Moscow, Russia.
  • 4 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
  • 5 Department of Pharmaceutical Chemistry, School of Health, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
  • 6 The Scientific Technological Center of Organic and Pharmaceutical Chemistry, Armenian Academy of Science, Institute of Fine Organic Chemistry of A.L. Mnjoyan, Avenue Azatutyan 26, Yerevan 0014, Armenia.
  • 7 Institute of Physical and Organic Chemistry, Southern Federal University, Pr. Stachki 194/2, 344090 Rostov-on-Don, Russia.
  • 8 Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Tandogan, Ankara 06100, Turkey.
  • 9 Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand.
  • 10 Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand.
PMID: 39639019 DOI: 10.1021/acs.jpcb.4c06246
Abstract

The treatment of patients with nonsmall cell lung Cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC50 values in the nanomolar range. Among these, PD18 and PD56 exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC50 values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

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