Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method

Michaux, Catherine; Leval, Xavier de; Julémont, Fabien; Dogné, Jean‐Michel; Pirotte, Bernard; Durant, François

doi:10.1016/j.ejmech.2006.07.017

Cited by 33 publications

(12 citation statements)

References 54 publications

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“…Therefore, we used aryl and alkyl groups substituents due to their hydrophobicity, pointed as a relevant feature to COX-1 selective inhibition when carboxylate groups are converted to less reactive acidic groups [ 18 ]. Co-substitutions of a potential lead molecule tailoring a HBA and a hydrophobic group was recently reported as an expressive approach for selective inhibition of cyclooxygenases, since it increases the molecular similarities to arachidonic acid by mimicking its 20-carbon hydrophobic ω-chain and the carboxylate group, which acts as a strong HBA group [ 25 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

“…The thiourea moiety has been described as an important pharmacophore in a variety of promising chemical prototypes for drug development, including: anti-HIV (inhibitors of HIV capsid assembly) [ 19 ], anticancer [ 20 ], anticonvulsant [ 21 ], antimycobacterial [ 22 ], anti-HCV [ 23 ] and antimicrobial agents [ 24 ]. Recently the thiourea moiety was described for dual inhibition of both cyclooxygenase isoforms 1 and 2 with a 4-fold selectivity towards COX-2 active site [ 25 ], pointing its anti-inflammatory properties. The antithrombotic activity of this class of molecules was also explored as antagonists of the thrombin receptor PAR1 [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

et al. 2015

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The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

et al. 2015

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“…HipHop attempts to derive a pharmacophore based on features that are common to active molecules. The constructed 3D pharmacophore model can be used for identiﬁcation of original lead compounds from a database [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

A Selective Pharmacophore Model for β2-Adrenoceptor Agonists

Xing

Wang

et al. 2009

Molecules

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β2-Adrenoceptor selectivity is an important consideration in drug design in order to minimize the possibility of side effects. A selective pharmacophore model was developed based on a series of selective β2-adrenoceptor agonists. The best pharmacophore hypothesis consisted of five chemical features (one hydrogen-bond acceptor, one hydrogen-bond donor, two ring aromatic and one positive ionizable feature). The result was nearly in accordance with the reported interactions between the β2-adrenoceptor and agonists, and it shared enough similar features with the result of field point patterns by FieldTemplater, which mainly validated the pharmacophore model. Moreover, the pharmacophore could predict the selectivity over the β1-adrenoceptor. These results might provide guidance for the rational design of novel potent and selective β2-adrenoceptor agonists.

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“…Currently, Kurogi and Guner [28] have employed Catalyst/HipHop generated pharmacophore method to identify novel mesangial cell proliferation inhibitors. Michaux et al [29] identified 16 diverse and highly cyclooxygenase-2 (COX-2) selective inhibitors by generating pharmacophore model via Catalyst/HipHop approach. These researches indicate that Catalyst/HipHop generated pharmacophore can be effectively used for identifying new potential lead candidates.…”

Section: Introductionmentioning

confidence: 99%

Insight into analysis of interactions of GW9508 to wild-type and H86F and H137F GPR40: A combined QM/MM study and pharmacophore modeling

Jiang

Zou

et al. 2011

Journal of Molecular Graphics and Modelling

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Structure-based pharmacophore of COX-2 selective inhibitors and identification of original lead compounds from 3D database searching method

Cited by 33 publications

References 54 publications

Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

A Selective Pharmacophore Model for β2-Adrenoceptor Agonists

Insight into analysis of interactions of GW9508 to wild-type and H86F and H137F GPR40: A combined QM/MM study and pharmacophore modeling

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