Skip to content

Targets

QligFEP has been used on different targets, examples can be found in the publications below.

GPCR: Adenosine A2A Receptor

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists
W. Jespers, G. Verdon, J. Azuaje, M. Majellaro, H. Keränen, X. García‐Mera, M. Congreve, F. Deflorian, C. de Graaf, A. Zhukov, A.S. Doré, J.S. Mason, J. Åqvist, R.M. Cooke, E. Sotelo, H. Gutiérrez‐de‐Terán, Angewandte Chemie International Edition 2020, 59 (38), 16536-16543.

In this project with Sosei-Heptares, our engines QligFEP and QresFEP were integrated with their Biophysical mapping (BMP) technology and X-ray crystallography, to assess on the design of new A2A antagonists synthesized by the Sotelo lab at USC.

GPCR: Adenosine A2B Receptor

3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor: Optimization, Structure–Activity Relationship Studies, and Enantiospecific recognition
M. Majellaro, W. Jespers, A. Crespo, M.J. Núñez, S. Novio, J. Azuaje, R. Prieto-Díaz, C. Gioé, B. Alispahic, J. Brea, M.I. Loza, M. Freire-Garabal, C. Garcia-Santiago, C. Rodríguez-García, X. García-Mera, O. Caamaño, C. Fernandez-Masaguer, J.F. Sardina, A. Stefanachi, A. El Maatougui, A. Mallo-Abreu, J. Åqvist, H. Gutiérrez-de-Terán, E. Sotelo, Journal of Medicinal Chemistry 2021, 64 (1), 458–480.

As part of a long-term established collaboration with the Sotelo ComBioMed lab at USC, we designed and analyzed a large library of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. For this, we performed one of the most exhaustive free energy perturbation (FEP) studies on a GPCR. As a result, a number of potent, selective and stereospecific A2B antagonists were reported, including results on in vitro experiments in three prostate cancer cells that evidenced that they exhibit a pronounced anti-metastatic effect.

GPCR: Adenosine A3 Receptor

Effect of Nitrogen Atom Substitution in A3 Adenosine Receptor Binding: N -(4,6-
Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
J. Azuaje, W. Jespers, V. Yaziji, A. Mallo, M. Majellaro, O. Caamaño, M.I. Loza, M.I. Cadavid, J. Brea, J. Åqvist, E. Sotelo, H. Gutiérrez-de-Terán, Journal of Medicinal Chemistry 2017, 60 (17), 7502-7511.

The computer-assisted design of the first family of 2-acetamidopyridines as potent and selective adenosine A3 receptor antagonists, was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. In this study we showed how MD and FEP simulations allowed to elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which was revealed as a stabilizer of a water network in the binding site.

Kinase: Human epidermal growth factor receptor 2 (HER2)

Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines
O. Cruz-López, M. Ner, F. Nerín-Fonz, Y. Jiménez-Martínez, D. Araripe, J. A. Marchal, H. Boulaiz, H. Gutiérrez-de-Terán, J. M. Campos, A. Conejo-García, Journal of Enzyme Inhibition and Medicinal Chemistry 2021, 36 (1), 1553–1563.

QligFEP was used to study the influence of methylation, the bioisosteric replacement of the purine by benzotriazole , and the introduction of a bulky substituent at position 6 of the purine, on the inhibition against HER2 of a series of benzoxazepine derivatives. The most potent compounds against isolated HER2 inhibit cell proliferation or promote pyroptosis, showing their interest in cancer therapies.

NNMT: Nicotinamide N-Methyltransferase

Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics.
Y. Gao, M. J. van Haren, N. Buijs, P. Innocenti, Y. Zhang, D. Sartini, R. Campagna, M. Emanuelli, R. B. Parsons, W. Jespers, H. Gutiérrez-de-Terán, G. J. P. van Westen, N. I. Martin, Journal of Medicinal Chemistry 2021, 64 (17), 12938–12963.

Modeling of Alkene-Linked Bisubstrate Mimics bearing the ortho-, meta-, and para-cyano substituents in the active site of NNMT. The FEP indicates the strong hydrogen bonding of the most potent para-cyano compound with two serine residues, absent in the other derivatives.