Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: Modulation at the N-portion and distal phenyl ring

Ortar, Giorgio; Morera, Enrico; Petrocellis, Luciano De; Ligresti, Alessia; Moriello, Aniello Schiano; Morera, Ludovica; Nalli, Marianna; Ragno, Rino; Pirolli, Adele; Marzo, Vincenzo Di

doi:10.1016/j.ejmech.2013.02.005

Cited by 16 publications

(12 citation statements)

References 69 publications

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“…The complexes were subjected to a cleaning procedure including removal of water molecules, ions and crystallization co-solutes and saved separated into ligand (key) and protein (lock). As all TR inhibitors were covalently bonded to Cys145, similarly as previously reported [ 59 , 60 ] they were converted to the corresponding pre-covalent complexes by rebuilding the non-reacted species by means of Chimera Build Structure plugin. Reconstituted inhibitors were merged in the corresponding proteins and the resulting complexes were energy minimized to relax steric clashes.…”

Section: Methodsmentioning

confidence: 96%

Ligand-based and structure-based studies to develop predictive models for SARS-CoV-2 main protease inhibitors through the 3d-qsar.com portal

Proia

Ragno

Antonini

et al. 2022

J Comput Aided Mol Des

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The main protease (Mpro) of SARS-Cov-2 is the essential enzyme for maturation of functional proteins implicated in viral replication and transcription. The peculiarity of its specific cleavage site joint with its high degree of conservation among all coronaviruses promote it as an attractive target to develop broad-spectrum inhibitors, with high selectivity and tolerable safety profile. Herein is reported a combination of three-dimensional quantitative structure–activity relationships (3-D QSAR) and comparative molecular binding energy (COMBINE) analysis to build robust and predictive ligand-based and structure-based statistical models, respectively. Models were trained on experimental binding poses of co-crystallized Mpro-inhibitors and validated on available literature data. By means of deep optimization both models’ goodness and robustness reached final statistical values of r2/q2 values of 0.97/0.79 and 0.93/0.79 for the 3-D QSAR and COMBINE approaches respectively, and an overall predictiveness values of 0.68 and 0.57 for the SDEPPRED and AAEP metrics after application to a test set of 60 compounds covered by the training set applicability domain. Despite the different nature (ligand-based and structure-based) of the employed methods, their outcome fully converged. Furthermore, joint ligand- and structure-based structure–activity relationships were found in good agreement with nirmatrelvir chemical features properties, a novel oral Mpro-inhibitor that has recently received U.S. FDA emergency use authorization (EUA) for the oral treatment of mild-to-moderate COVID-19 infected patients. The obtained results will guide future rational design and/or virtual screening campaigns with the aim of discovering new potential anti-coronavirus lead candidates, minimizing both time and financial resources. Moreover, as most of calculation were performed through the well-established web portal 3d-qsar.com the results confirm the portal as a useful tool for drug design. Graphical abstract

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Section: Methodsmentioning

confidence: 96%

Ligand-based and structure-based studies to develop predictive models for SARS-CoV-2 main protease inhibitors through the 3d-qsar.com portal

Proia

Ragno

Antonini

et al. 2022

J Comput Aided Mol Des

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“…IC 50 value can also be used to describe the functional strength of the inhibitors. In addition, considering the measures of the effectiveness of compound inhibition towards enzymes, IC 50 value is universally used to qualitatively and quantitatively symbolize the inhibitory effect of compounds in pharmacological research in vitro and to evaluate the FAAH inhibitory effect of compounds commonly [8,46,48]. To confirm the direct interaction between NsTyr and FAAH, we tested FAAH activity in the presence of NsTyr by using an assay kit.…”

Section: Nstyr Has Direct and Indirect Effects On Faahmentioning

confidence: 99%

N-stearoyltyrosine protects primary cortical neurons against Aβ(1–40)-induced injury through inhibiting endocannabinoid degradation

Cui

Yang

et al. 2015

Life Sciences

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“…The option for modified energy evaluation was apparently not available for AutoDock Vina , for which a workaround was used to exploit the side chain flexibility function for covalent docking of biaryl tetrazolyl ureas to fatty acid amide hydrolase (FAAH) . The inhibitors were bound to the serine nucleophile in their transition‐state form, and a water molecule was docked to the protein while setting the modified residue side chain as flexible.…”

Section: Modeling Covalent Bond Formation In Docking Approachesmentioning

confidence: 99%

“…The question remains whether an optimal solution can generally be ensured by such a setting, because the docking process will primarily search for optimal placements of the water molecule. Nevertheless, for the test set of 14 cocrystallized FAAH inhibitors, the experimental binding mode was very well reproduced in redocking experiments …”

Section: Modeling Covalent Bond Formation In Docking Approachesmentioning

confidence: 99%

Docking of Covalent Ligands: Challenges and Approaches

Sotriffer

2018

Molecular Informatics

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Covalent ligands have recently regained considerable attention in drug discovery. The rational design of such ligands, however, is still faced with particular challenges, mostly related to the fact that covalent bond formation is a quantum mechanical phenomenon which cannot adequately be handled by the force fields or empirical approaches typically used for noncovalent protein-ligand interactions. Although the necessity for quantum chemical approaches is clear, they cannot yet routinely be applied on large data sets of ligands or for a broader exploration of binding modes in docking calculations. On the other hand, technical solutions for performing docking calculations with covalent ligands are available, but their scope is normally quite limited. Scoring functions typically neglect the contribution from covalent bond formation completely. In this situation, the question arises how to approach covalent ligands and which methods to choose for their docking and design.

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Biaryl tetrazolyl ureas as inhibitors of endocannabinoid metabolism: Modulation at the N-portion and distal phenyl ring

Cited by 16 publications

References 69 publications

Ligand-based and structure-based studies to develop predictive models for SARS-CoV-2 main protease inhibitors through the 3d-qsar.com portal

Ligand-based and structure-based studies to develop predictive models for SARS-CoV-2 main protease inhibitors through the 3d-qsar.com portal

N-stearoyltyrosine protects primary cortical neurons against Aβ(1–40)-induced injury through inhibiting endocannabinoid degradation

Docking of Covalent Ligands: Challenges and Approaches

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