Retrospective group fusion similarity search based on eROCE evaluation metric

Avram, Sorin; Crisan, Luminita; Bora, Alina; Pacureanu, Liliana; Avram, Speranța; Kurunczi, Ludovic

doi:10.1016/j.bmc.2012.12.041

Cited by 12 publications

(21 citation statements)

References 45 publications

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“…This was performed by using in vitro COX inhibitor screening assays. Furthermore, molecular docking studies were performed in order to predict the binding mode of compounds A1 – 13 , based on our previous expertise in this field [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles

et al. 2017

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Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used therapeutic agents that exhibit frequent and sometimes severe adverse effects, including gastrointestinal ulcerations and cardiovascular disorders. In an effort to obtain safer NSAIDs, we assessed the direct cyclooxygenase (COX) inhibition activity and we investigated the potential COX binding mode of some previously reported 2-(trimethoxyphenyl)-thiazoles. The in vitro COX inhibition assays were performed against ovine COX-1 and human recombinant COX-2. Molecular docking studies were performed to explain the possible interactions between the inhibitors and both COX isoforms binding pockets. Four of the tested compounds proved to be good inhibitors of both COX isoforms, but only compound A3 showed a good COX-2 selectivity index, similar to meloxicam. The plausible binding mode of compound A3 revealed hydrogen bond interactions with binding site key residues including Arg120, Tyr355, Ser530, Met522 and Trp387, whereas hydrophobic contacts were detected with Leu352, Val349, Leu359, Phe518, Gly526, and Ala527. Computationally predicted pharmacokinetic profile revealed A3 as lead candidate. The present data prove that the investigated compounds inhibit COX and thus confirm the previously reported in vivo anti-inflammatory screening results suggesting that A3 is a suitable candidate for further development as a NSAID.

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Section: Introductionmentioning

confidence: 99%

COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles

et al. 2017

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“…39 Rho-associated protein kinase 1. 40 Serine/threonine-protein kinase pim-2. 41 Cell division cycle 7-related protein kinase.…”

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confidence: 99%

Predictive Models for Fast and Effective Profiling of Kinase Inhibitors

Bora

Avram

Ciucanu

et al. 2016

J. Chem. Inf. Model.

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In this study we developed two-dimensional pharmacophore-based random forest models for the effective profiling of kinase inhibitors. One hundred seven prediction models were developed to address distinct kinases spanning over all kinase groups. Rigorous external validation demonstrates excellent virtual screening and classification potential of the predictors and, more importantly, the capacity to prioritize novel chemical scaffolds in large chemical libraries. The models built upon more diverse and more potent compounds tend to exert the highest predictive power. The analysis of ColBioS-FlavRC (Collection of Bioselective Flavonoids and Related Compounds) highlighted several potentially promiscuous derivatives with undesirable selectivity against kinases. The prediction models can be downloaded from www.chembioinf.ro .

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“…Each LBVS experiment employing 3D similarity search with ROCS and EON was validated according to acknowledged virtual screening assessment parameters (ROC‐AUC) and eROCE in a concerted way since none of them is a flawless indicator of ranking performance. Receiver operating characteristic curve – area under the curve (ROC‐AUC) was used to evaluate LBVS experiments .…”

Section: Methodsmentioning

confidence: 99%

“…Receiver operating characteristic curve – area under the curve (ROC‐AUC) was used to evaluate LBVS experiments . Since “early enrichment” cannot be well illustrated by AUC, even at higher AUC values, an evaluation parameter introduced by our group eROCE involves a multi‐grade‐FPR weighting system, seeking to smooth the effect of hard cutoffs by attributing decreasing weights to each „active” detected along the hierarchical list . We generated heatmaps to suggest meaningful differences in the AUC and eROCE values.…”

Section: Methodsmentioning

confidence: 99%

Partial Least Squares Discriminant Analysis and 3D Similarity Perspective Applied to Analyze Comprehensively the Selectivity of Glycogen Synthase Kinase 3 Inhibitors

Crisan

Avram

Kurunczi

et al. 2020

Molecular Informatics

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The current work was conducted to investigate the effectiveness of two conceptually distinct in silico ligand-based tools: Partial Least Squares Discriminant Analysis (PLS-DA) and 3D similarity, including shape, physico-chemical and electrostatics to classify target-specific pharmacophores with enrichment power for selective GSK-3 inhibitors against the phylogenetically related CDK-2, CDK-4, CDK-5 and PKC. All virtual screens were performed on four data sets of targets matched pairwise, including selective and nonselective inhibitors for GSK-3. The classification method PLS-DA results revealed that all obtained models are statistically robust according to the crossvalidation and response permutation tests. Regarding selective GSK-3 inhibitors differentiation in terms of selectivity (Se), specificity (Sp), and accuracy (ACC), the PLS-DA models for CDK-4/GSK-3, and PKC/GSK-3 datasets are highly efficient discriminative. 3D similarity searches for CDK-4/GSK-3, PKC/GSK-3, and CDK-2/GSK-3 datasets using the most selective reference molecules lead to highest enrichments of selective GSK-3 inhibitors. EON yields excellent early and overall enrichments for ET_ST and ET_ combo for most selective query for CDK-4/GSK-3. CDK-5/ GSK-3 dataset didn't show consistent statistically significant enrichments for 3D similarity virtual screening. The current methodology is reliable and could be used as a powerful tool for the detection of potentially selective molecules targeting GSK-3.

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Retrospective group fusion similarity search based on eROCE evaluation metric

Cited by 12 publications

References 45 publications

COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles

COX Inhibition Profile and Molecular Docking Studies of Some 2-(Trimethoxyphenyl)-Thiazoles

Predictive Models for Fast and Effective Profiling of Kinase Inhibitors

Partial Least Squares Discriminant Analysis and 3D Similarity Perspective Applied to Analyze Comprehensively the Selectivity of Glycogen Synthase Kinase 3 Inhibitors

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