Dual-Target Virtual Screening by Pharmacophore Elucidation and Molecular Shape Filtering

Moser, Daniel; Wiśniewska, Joanna; Hahn, Steffen; Achenbach, Janosch; Buscató, Estel·la; Klingler, Franca‐Maria; Hofmann, Bettina; Steinhilber, Dieter; Proschak, Ewgenij

doi:10.1021/ml200286e

Cited by 44 publications

(34 citation statements)

References 21 publications

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“…5-LOX/sEH dual inhibitors have been recently discovered by dual-target virtual screening using an in silico approach [187]. Among the eighty compounds selected by the virtual screening, thirty six compounds have been tested with in vitro enzyme assays.…”

Section: Rationally Designed Multitarget Agentsmentioning

confidence: 99%

Rationally Designed Multitarget Agents Against Inflammation and Pain

Hwang

Wecksler

Wagner

et al. 2013

CMC

101

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Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.

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Section: Rationally Designed Multitarget Agentsmentioning

confidence: 99%

Rationally Designed Multitarget Agents Against Inflammation and Pain

Hwang

Wecksler

Wagner

et al. 2013

CMC

101

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“…A more detailed analysis of performance of these methods will be presented below following a description of the methodological approaches, but a few representative examples from the recent literature are provided here to give an indication of their capabilities. A ligand‐based VS protocol that included molecular shape filtering identified nine novel inhibitors of 5‐lipoxygenase/soluble epoxide lyase with activities in the low micromolar range 1. Database searching of a library of over 2 million compounds using shape‐based VS identified novel, nonsteroidal, micromolar actives against the insect molting hormone receptor using a steroidal query molecule, ponasterone A 2.…”

Section: Introductionmentioning

confidence: 99%

Shape‐based similarity searching in chemical databases

Finn

Morris

2012

WIREs Comput Mol Sci

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Shape similarity is a key concept and requirement for molecular recognition. As a result, much research has been undertaken to develop methods to represent molecular shape and to quantify the shape similarity between molecules. A great variety of shape descriptions and similarity comparison approaches have been developed, ranging from explicit representations using intersecting atom-centered spheres and molecular superposition to abstract statistical representations that allow alignment-free comparisons. Several of these methods have sufficient computational performance to allow shape similarity searches over extremely large compound databases as a ligand-based virtual screening (VS) technique. As with other approaches to VS, the relative performance of shape similarity methods is dataset and problem specific, with each approach having its merits and limitations and no one approach showing a clear and consistent advantage over the others. Again, as with other VS approaches, most reports of performance are in the context of retrospective validation studies, which show competitive performance against target-based and two-dimensional methods. Prospective studies are rarer in the literature, but a number of successes have been reported. Intensive research continues in the search for improved representations of shape, partial shape matching, and approaches to address the challenges imposed by ligand and target flexibility. C 2012 John Wiley & Sons, Ltd.

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“…After the closing phase of this project, 2‐phenylbenzimidazole and related derivatives were reported as fragment hits for sEH on the basis of elaborate in silico approaches . Whereas the best 2‐phenylbenzimidazole compound from those in silico screenings has a potency in the low micromolar range, compound 16 as a representative of our 2‐phenylbenzimidazole‐4‐sulfonamides has significantly higher potency (IC 50 =17 n m ).…”

Section: Resultsmentioning

confidence: 99%

“…After the closing phase of this project, 2-phenylbenzimidazole and relatedd erivatives were reported as fragment hits for sEH on the basis of elaborate in silico approaches. [27,43] Whereas the best 2-phenylbenzimidazole compound from those in silico screenings has ap otency in the low micromolar range, compound 16 as ar epresentative of our 2-phenylbenzimidazole-4sulfonamides has significantly higher potency( IC 50 = 17 nm). More importantly,t he induced-fit features associated with the 2-phenylbenzimidazole-4-sulfonamide scaffolda sr evealed by high-resolution crystal structures present distinct novel interactions with sEH.…”

Section: -Phenylbenzimidazole-4-sulfonamide Was Identified As Ah It mentioning

confidence: 98%

Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation—Structure‐Based Hit Evaluation and Chemistry Exploration

et al. 2016

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Soluble epoxide hydrolase (sEH) is involved in the regulation of many biological processes by metabolizing the key bioactive lipid mediator, epoxyeicosatrienoic acids. For the development of sEH inhibitors with improved physicochemical properties, we performed both a fragment screening and a high-throughput screening aiming at an integrated hit evaluation and lead generation. Followed by a joint dose-response analysis to confirm the hits, the identified actives were then effectively triaged by a structure-based hit-classification approach to three prioritized series. Two distinct scaffolds were identified as tractable starting points for potential lead chemistry work. The oxoindoline series bind at the right-hand side of the active-site pocket with hydrogen bonds to the protein. The 2-phenylbenzimidazole-4-sulfonamide series bind at the central channel with significant induced fit, which has not been previously reported. On the basis of the encouraging initial results, we envision that a new lead series with improved properties could be generated if a vector is found that could merge the cyclohexyl functionality of the oxoindoline series with the trifluoromethyl moiety of the 2-phenylbenzimidazole-4-sulfonamide series.

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Dual-Target Virtual Screening by Pharmacophore Elucidation and Molecular Shape Filtering

Cited by 44 publications

References 21 publications

Rationally Designed Multitarget Agents Against Inflammation and Pain

Rationally Designed Multitarget Agents Against Inflammation and Pain

Shape‐based similarity searching in chemical databases

Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation—Structure‐Based Hit Evaluation and Chemistry Exploration

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