| 1. |
- Matricon, Pierre, et al.
(author)
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Fragment optimization for GPCRs by molecular dynamics free energy calculations : Probing druggable subpockets of the A(2A) adenosine receptor binding site
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A(2A) adenosine receptor, a pharmaceutically relevant G protein-coupled receptor. Optimization of fragments exploring two binding site subpockets was probed by calculating relative binding affinities for 23 adenine derivatives, resulting in strong agreement with experimental data (R-2 = 0.78). The predictive power of MD/FEP was significantly better than that of an empirical scoring function. We also demonstrated the potential of the MD/FEP to assess multiple binding modes and to tailor the thermodynamic profile of ligands during optimization. Finally, MD/FEP was applied prospectively to optimize three nonpurine fragments, and predictions for 12 compounds were evaluated experimentally. The direction of the change in binding affinity was correctly predicted in a majority of the cases, and agreement with experiment could be improved with rigorous parameter derivation. The results suggest that MD/FEP will become a powerful tool in structure-driven optimization of fragments to lead candidates.
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| 2. |
- Rodriguez, David, et al.
(author)
-
Molecular Docking Screening Using Agonist-Bound GPCR Structures : Probing the A(2A) Adenosine Receptor
- 2015
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In: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 55:3, s. 550-563
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Journal article (peer-reviewed)abstract
- Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A(2A) adenosine receptor (A(2A)AR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A(2A)AR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A(2A)AR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A(2A)AR agonists and general strategies for structure-based drug discovery.
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| 3. |
- Rodriguez, David, et al.
(author)
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Structure-Based Screening of Uncharted Chemical Space for Atypical Adenosine Receptor Agonists
- 2016
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 11:10, s. 2763-2772
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Journal article (peer-reviewed)abstract
- Small molecule screening libraries cover only a small fraction of the astronomical number of possible drug-like compounds, limiting the success of ligand discovery efforts. Computational screening of virtual libraries representing unexplored chemical space could potentially bridge this gap. Drug development for adenosine receptors (ARs) as targets for inflammation and cardiovascular diseases has been hampered by the paucity of agonist scaffolds. To identify novel AR agonists, a virtual library of synthetically tractable nucleosides with alternative bases was generated and structure-based virtual screening guided selection of compounds for synthesis. Pharmacological assays were carried out at three AR subtypes for 13 ribosides. Nine compounds displayed significant activity at the ARs, and several of these represented atypical agonist scaffolds. The discovered ligands also provided insights into receptor activation and revealed unknown interactions of endogenous and clinical compounds with the ARs. The results demonstrate that virtual compound databases provide access to bioactive matter from regions of chemical space that are sparsely populated in commercial libraries, an approach transferrable to numerous drug targets.
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