| 1. |
- 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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| 2. |
- Bongers, B. J., et al.
(författare)
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Pan-cancer functional analysis of somatic mutations in G protein-coupled receptors
- 2022
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- G Protein-coupled receptors (GPCRs) are the most frequently exploited drug target family, moreover they are often found mutated in cancer. Here we used a dataset of mutations found in patient samples derived from the Genomic Data Commons and compared it to the natural human variance as exemplified by data from the 1000 genomes project. We explored cancer-related mutation patterns in all GPCR classes combined and individually. While the location of the mutations across the protein domains did not differ significantly in the two datasets, a mutation enrichment in cancer patients was observed among class-specific conserved motifs in GPCRs such as the Class A "DRY" motif. A Two-Entropy Analysis confirmed the correlation between residue conservation and cancer-related mutation frequency. We subsequently created a ranking of high scoring GPCRs, using a multi-objective approach (Pareto Front Ranking). Our approach was confirmed by re-discovery of established cancer targets such as the LPA and mGlu receptor families, but also discovered novel GPCRs which had not been linked to cancer before such as the P2Y Receptor 10 (P2RY10). Overall, this study presents a list of GPCRs that are amenable to experimental follow up to elucidate their role in cancer.
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| 3. |
- Burggraaff, Lindsey, et al.
(författare)
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Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors
- 2020
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 60:9, s. 4283-4295
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Tidskriftsartikel (refereegranskat)abstract
- Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 mu M) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC(50) value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well.
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| 4. |
- Gao, Yongzhi, et al.
(författare)
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Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:17, s. 12938-12963
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Tidskriftsartikel (refereegranskat)abstract
- Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-L-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
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| 5. |
- Henschel, Henning, et al.
(författare)
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Theoretical Infrared Spectra : Quantitative Similarity Measures and Force Fields
- 2020
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Ingår i: Journal of Chemical Theory and Computation. - : AMER CHEMICAL SOC. - 1549-9618 .- 1549-9626. ; 16:5, s. 3307-3315
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Tidskriftsartikel (refereegranskat)abstract
- Infrared spectroscopy can provide significant insight into the structures and dynamics of molecules of all sizes. The information that is contained in the spectrum is, however, often not easily extracted without the aid of theoretical calculations or simulations. We present here the calculation of the infrared spectra of a database of 703 gas phase compounds with four different force fields (CGenFF, GAFF-BCC, GAFF-ESP, and OPLS) using normal-mode analysis. Modern force fields increasingly use virtual sites to describe, e.g., lone-pair electrons or the o -holes on halogen atoms. This requires some adaptation of code to perform normal-mode analysis of such compounds, the implementation of which into the GROMACS software is briefly described as well. For the quantitative comparison of the obtained spectra with experimental reference data, we discuss the application of two different statistical correlation coefficients, Pearson and Spearman. The advantages and drawbacks of the different methods of comparison are discussed, and we find that both methods of comparison give the same overall picture, showing that present force field methods cannot match the performance of quantum chemical methods for the calculation of infrared spectra.
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| 6. |
- Jandova, Zuzana, et al.
(författare)
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Free-Energy Calculations for Bioisosteric Modifications of A(3) Adenosine Receptor Antagonists
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 20:14
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Tidskriftsartikel (refereegranskat)abstract
- Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A(3) adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol.
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| 7. |
- Jespers, Willem, et al.
(författare)
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Deciphering conformational selectivity in the A(2A) adenosine G protein-coupled receptor by free energy simulations
- 2021
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- Transmembranal G Protein-Coupled Receptors (GPCRs) transduce extracellular chemical signals to the cell, via conformational change from a resting (inactive) to an active (canonically bound to a G-protein) conformation. Receptor activation is normally modulated by extracellular ligand binding, but mutations in the receptor can also shift this equilibrium by stabilizing different conformational states. In this work, we built structure-energetic relationships of receptor activation based on original thermodynamic cycles that represent the conformational equilibrium of the prototypical A(2A) adenosine receptor (AR). These cycles were solved with efficient free energy perturbation (FEP) protocols, allowing to distinguish the pharmacological profile of different series of A(2A)AR agonists with different efficacies. The modulatory effects of point mutations on the basal activity of the receptor or on ligand efficacies could also be detected. This methodology can guide GPCR ligand design with tailored pharmacological properties, or allow the identification of mutations that modulate receptor activation with potential clinical implications.
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| 8. |
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| 9. |
- Jespers, Willem
(författare)
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Free energy calculations of G protein-coupled receptor modulation : New methods and applications
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- G protein-coupled receptors (GPCRs) are membrane proteins that transduce the signals of extracellular ligands, such as hormones, neurotransmitters and metabolites, through an intracellular response via G proteins. They are abundant in human physiology and approximately 34% of the marketed drugs target a GPCR. Upon activation, the receptor undergoes conformational changes to accommodate the binding of the G protein. Our insights in the structural determinants of ligand binding and receptor activation have increased tremendously over the past decade. This has largely been a cause of the growing amount of experimentally determined structures, which provide crucial insights in ligand binding mechanisms. However, in a typical drug design project it is unlikely that such structures can be generated for all ligands. In those cases, computationally derived models of the protein-ligand complex can be generated. Rigorous free energy calculations such as the free energy perturbation (FEP) method, can subsequently provide the missing link between those structures and experimental ligand binding data, and provide further insights in the binding mechanism.In this thesis, two workflows are presented to calculate free energies of binding for ligands to wildtype (QligFEP) and mutant (QresFEP) receptors. Both methods were tested on a set of solvation free energies of sidechain mimics. QligFEP was furthermore applied on three protein-ligand binding datasets, including pair comparisons between topologically unrelated molecules (scaffold hopping). QresFEP was used to calculate protein-ligand binding affinities to mutants of the neuropeptide Y1, and to predicte the effect of receptor modifications on the thermal stability of T4 lysozyme.The remainder of this work focussed on the application of these protocols in the design, synthesis and molecular pharmacology of ligands for the family of adenosine receptor (ARs). These receptors, involved in many physiological processes such as promotion of sleep (caffeine is a well-known inhibitor), have recently been pursued as drug targets in immuno-oncology. QligFEP was used in the design of novel series of antagonists for the A3AR and A2BAR. QresFEP was used to study ligand binding to the A1AR and in a multidisciplinary approach to characterize binding to the orphan receptor GPR139. Both approaches were combined to design a series of A2AAR antagonist, and to propose a binding mode later confirmed by new crystal structures. Finally, a new application of FEP is introduced based on conformational equilibria between the active and inactive A2AAR, to elucidate the regulation mechanism of receptor activation by ligands and receptor mutations.
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| 10. |
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