| 1. |
- Jespers, Willem, et al.
(författare)
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X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A(2A) Adenosine Receptor Antagonists
- 2020
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Ingår i: Angewandte Chemie International Edition. - : WILEY-V C H VERLAG GMBH. - 1433-7851 .- 1521-3773. ; 59:38, s. 16536-16543
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Tidskriftsartikel (refereegranskat)abstract
- We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the A(2A) adenosine receptor (AR). Eight A(2A)AR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A(2A)AR were experimentally determined and investigated through a cycle of ligand-FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A(2A)AR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A(2A)AR, an emerging target in immunooncology.
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| 2. |
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| 3. |
- Prieto-Diaz, Ruben, et al.
(författare)
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Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists : Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
- 2024
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Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 173
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Tidskriftsartikel (refereegranskat)abstract
- Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.
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| 4. |
- Prieto-Díaz, Rubén, et al.
(författare)
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Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:1, s. 890-912
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Tidskriftsartikel (refereegranskat)abstract
- The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
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| 5. |
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| 6. |
- Rodriguez-Espigares, Ismael, et al.
(författare)
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GPCRmd uncovers the dynamics of the 3D-GPCRome
- 2020
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Ingår i: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 17:8, s. 777-787
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Tidskriftsartikel (refereegranskat)abstract
- G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
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| 7. |
- Agullo, Luis, et al.
(författare)
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Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase
- 2016
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Ingår i: Proteins. - : Wiley. - 0887-3585 .- 1097-0134. ; 84:10, s. 1534-1548
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Tidskriftsartikel (refereegranskat)abstract
- Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an in silico approach. Homology models of the catalytic domain of sGC in inactive or active conformations were constructed using the structure of previously described crystals of the catalytic domains of inactive sGCs (2WZ1, 3ET6) and of active adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 s. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of inactive and active conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the active structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop (2)-(3), does not overlap with the forskolin binding site on adenylate cyclases.
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| 8. |
- Azuaje, Jhonny, et al.
(författare)
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Effect of Nitrogen Atom Substitution in A(3) Adenosine Receptor Binding : N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
- 2017
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 60:17, s. 7502-7511
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Tidskriftsartikel (refereegranskat)abstract
- We report the first family of 2-acetamidopyridines as potent and selective A, adenosine receptor (AR) antagonists. The computer -assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (K-j < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA(3)AR, and exemplifies the benefits of a joint theoretical- experimental approach to identify novel hA(3)AR antagonists through succinct and efficient synthetic methodologies.
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| 9. |
- Azuaje, Jhonny, et al.
(författare)
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Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists
- 2015
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Ingår i: Future Medicinal Chemistry. - : Future Science Ltd. - 1756-8919 .- 1756-8927. ; 7:11, s. 1373-1380
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Tidskriftsartikel (refereegranskat)abstract
- Background: A(3)AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A(3)AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A(3)AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A(3)AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure-activity and structure-selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.
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| 10. |
- Barlow, Nicholas, et al.
(författare)
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Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
- 2020
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Ingår i: RSC Medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 11:2, s. 234-244
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Tidskriftsartikel (refereegranskat)abstract
- Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (∆G) and relative binding free energies (∆∆G) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.
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