Editors' ChoiceDrug Screening

New connections: From virtual screening to biological reality

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Science Signaling  31 May 2016:
Vol. 9, Issue 430, pp. ec128
DOI: 10.1126/scisignal.aag2260

Screening compounds for biological activity computationally has the potential to speed the rate of scientific discovery. One common approach is molecular dynamics simulation (MDS), which relies on structural models of the target and chemical models of the putative ligands. Possible configurations that enable the ligand to dock (associate) with the target are simulated until one or more with a biologically reasonable energy profile is found. In a real biological system, the molecules will not have an infinite opportunity to find just the right fit, so MDS interactions must be tested in a physiological context to determine if the docking interaction is biologically relevant and if the docked ligand affects the target’s activity or function. In this week’s issue, Wardman et al. used structural modeling and virtual molecule docking to identify candidate ligands for the G protein–coupled receptor GPR171. One of these, MS0015203, selectively bound to GPR171 and required GPR171 to stimulate a response in cultured cells and in mice. Mice receiving this drug by injection into the periphery ate more and had increased body weight, and both responses depended on GPR171. A pair of papers from the Archives illustrates additional applications of virtual screening to discover regulators of signaling processes. Corral-Lugo et al. used in silico docking screening to identify candidate molecules from plants that bound to the bacterial quorum–sensing regulator RhlR from the pathogenic bacterium Pseudomonas aeruginosa. Subsequent analysis with bacteria showed that the candidate compound, rosmarinic acid, stimulated RhlR activity, thereby functioning as a mimic of the bacterial quorum–sensing ligands. Identification of this molecular mimic has both agricultural and biomedical implications by enabling strategic disruption of bacterial communication. Matsoukas et al. performed a virtual screen of a chemical database (>5 million compounds) to identify candidate compounds that may function as immunosuppressants with fewer side effects than those of drugs that inhibit the catalytic activity of the phosphatase calcineurin. The authors screened for small molecules that bound to the same region of calcineurin to which the transcription factor NFAT binds, with the goal of identifying molecules that could selectively disrupt NFAT activation without affecting the activity of calcineurin for its other targets. The screen identified multiple candidates, which were further selected by in vitro analysis for their ability to displace NFAT from calcineurin-NFAT complexes without inhibiting the activity of the phosphatase. Four of the subset with desired in vitro activity blocked the expression of NFAT-dependent genes in human T cells and inhibited T cell proliferation in culture, suggesting that these may be good leads for further testing as immunosuppressants.

J. H. Wardman, I. Gomes, E. N. Bobeck, J. A. Stockert, A. Kapoor, P. Bisignano, A. Gupta, M. Mezei, S. Kumar, M. Filizola, L. A. Devi, Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci. Signal. 9, ra55 (2016). [Abstract]

A. Corral-Lugo, A. Daddaoua, A. Ortega, M. Espinosa-Urgel, T. Krell, Rosmarinic acid is a homoserine lactone mimic produced by plants that activates a bacterial quorum-sensing regulator. Sci. Signal. 9, ra1 (2016). [Abstract]

M.-T. Matsoukas, Á. Aranguren-Ibáñez, T. Lozano, V. Nunes, J. J. Lasarte, L. Pardo, M. Pérez-Riba, Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners. Sci. Signal. 8, ra63 (2015). [Abstract]

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