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Bioisosteric Matrices for Ligands of Serotonin Receptors
2015
ChemMedChem
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Warszycki bioisosteres belonging to the same class of ligandsw ereg athered into matrices, revealing the amounto fp ositive, neutral and negative substitutions in terms of affinity towards ag iven target ...
doi:10.1002/cmdc.201402563
pmid:25772514
pmcid:PMC4471634
fatcat:v6lu4ksq5rfozdn73hd5sjk6ye
In Silico Methods for the Discovery of Orthosteric GABAB Receptor Compounds
2019
Molecules
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The GABAB receptor (GABAB-R) is a heterodimeric class C G protein-coupled receptor comprised of the GABAB1a/b and GABAB2 subunits. The endogenous orthosteric agonist γ-amino-butyric acid (GABA) binds within the extracellular Venus flytrap (VFT) domain of the GABAB1a/b subunit. The receptor is associated with numerous neurological and neuropsychiatric disorders including learning and memory deficits, depression and anxiety, addiction and epilepsy, and is an interesting target for new drug
doi:10.3390/molecules24050935
fatcat:fvp2k6ddzvgt7eibhtprra7yga
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... ment. Ligand- and structure-based virtual screening (VS) are used to identify hits in preclinical drug discovery. In the present study, we have evaluated classical ligand-based in silico methods, fingerprinting and pharmacophore mapping and structure-based in silico methods, structure-based pharmacophores, docking and scoring, and linear interaction approximation (LIA) for their aptitude to identify orthosteric GABAB-R compounds. Our results show that the limited number of active compounds and their high structural similarity complicate the use of ligand-based methods. However, by combining ligand-based methods with different structure-based methods active compounds were identified in front of DUDE-E decoys and the number of false positives was reduced, indicating that novel orthosteric GABAB-R compounds may be identified by a combination of ligand-based and structure-based in silico methods.
Average Information Content Maximization—A New Approach for Fingerprint Hybridization and Reduction
2016
PLoS ONE
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Fingerprints, bit representations of compound chemical structure, have been widely used in cheminformatics for many years. Although fingerprints with the highest resolution display satisfactory performance in virtual screening campaigns, the presence of a relatively high number of irrelevant bits introduces noise into data and makes their application more timeconsuming. In this study, we present a new method of hybrid reduced fingerprint construction, the Average Information Content
doi:10.1371/journal.pone.0146666
pmid:26784447
pmcid:PMC4718645
fatcat:r4yc3hkgsrbgzay72pnttve3uy
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... algorithm (AIC-MAX ALGORITHM), which selects the most informative bits from a collection of fingerprints. This methodology, applied to the ligands of five cognate serotonin receptors (5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT 5A , 5-HT 6 ), proved that 100 bits selected from four non-hashed fingerprints reflect almost all structural information required for a successful in silico discrimination test. A classification experiment indicated that a reduced representation is able to achieve even slightly better performance than the state-of-the-art 10-times-longer fingerprints and in a significantly shorter time.
Asymmetric Clustering Index in a Case Study of 5-HT1A Receptor Ligands
2014
PLoS ONE
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These indices were evaluated based on the reference reported by Warszycki et al. ...
As a reference, the manually constructed partition of Warszycki [5] was utilized. ...
doi:10.1371/journal.pone.0102069
pmid:25019251
pmcid:PMC4096758
fatcat:lbn2h35ixrdhpo4qj6y5yfqvhm
Ligand-guided homology modelling of the GABAB2 subunit of the GABAB receptor
2017
PLoS ONE
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OPEN ACCESS Citation: Freyd T, Warszycki D, Mordalski S, Bojarski AJ, Sylte I, Gabrielsen M (2017) Ligandguided homology modelling of the GABA B2 subunit of the GABA B receptor. ...
doi:10.1371/journal.pone.0173889
pmid:28323850
pmcid:PMC5360267
fatcat:jlshyjqmrzghxpp6miufgpqiri
Rational design of 5-HT6R ligands using a bioisosteric strategy: synthesis, biological evaluation and molecular modelling
2015
RSC Advances
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A bioisosteric strategy was successfully implemented with a screening protocol for new, potent 5-HT6R ligands.
doi:10.1039/c5ra00054h
fatcat:jrw34yc7azbx5eqnkhqkdrloga
Pyrano[2,3,4-cd]indole as a Scaffold for Selective Nonbasic 5-HT6R Ligands
2017
ACS Medicinal Chemistry Letters
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In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through a tandem bioisostere generation/virtual screening protocol in search of 5-HT6R ligands. The discovered chemical scaffold resulted in the design of highly active basic and nonbasic 5-HT6R ligands (5-HT6R Ki = 1 nM for basic compound 6b and 5-HT6R Ki = 4 nM for its neutral analog 7b). Additionally, molecular modeling suggested that the hydroxyl group of nonbasic ligands 7a-7d forms hydrogen bonds with aspartic acid D3×32 or D7.36×35.
doi:10.1021/acsmedchemlett.6b00482
pmid:28435524
pmcid:PMC5392774
fatcat:atzofyes4ze3rdsm2kqmeaorvm
Practical application of the Average Information Content Maximization (AIC-MAX) algorithm: selection of the most important structural features for serotonin receptor ligands
2017
Molecular diversity
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The Average Information Content Maximization algorithm (AIC-MAX) based on mutual information maximization was recently introduced to select the most discriminatory features. Here, this methodology was applied to select the most significant bits from the Klekota-Roth fingerprint for serotonin receptors ligands as well as to select the most important features for distinguishing ligands with activity for one receptor versus another. The interpretation of selected bits and machine-learning
doi:10.1007/s11030-017-9729-8
pmid:28185036
pmcid:PMC5438429
fatcat:eqks3xtyynesjerc64aphqlwwm
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... ts performed using the reduced interpretations outperformed the raw fingerprints and indicated the most important structural features of the analyzed ligands in terms of activity and selectivity. Moreover, the AIC-MAX methodology applied here for serotonin receptor ligands can also be applied to other target classes.
Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues
2021
Pharmaceuticals
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Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic 'caps' possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on
doi:10.3390/ph14090851
pmid:34577551
fatcat:m3kwxeefn5eqlkoyujxvic5tma
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... -6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment.
The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond
2018
RSC Advances
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The impact of weak intramolecular C–H⋯O interactions on the conformational stability of bis-arylsulfones is discussed, suggesting different role of sulfonyl group in the ligand – 5HT6 receptor interaction.
doi:10.1039/c8ra03107j
pmid:35541096
pmcid:PMC9080534
fatcat:s2w7kyezyzhpnhsfcw7aejqlge
A Linear Combination of Pharmacophore Hypotheses as a New Tool in Search of New Active Compounds – An Application for 5-HT1A Receptor Ligands
2013
PLoS ONE
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This study explores a new approach to pharmacophore screening involving the use of an optimized linear combination of models instead of a single hypothesis. The implementation and evaluation of the developed methodology are performed for a complete known chemical space of 5-HT 1A R ligands (3616 active compounds with K i < 100 nM) acquired from the ChEMBL database. Clusters generated from three different methods were the basis for the individual pharmacophore hypotheses, which were assembled
doi:10.1371/journal.pone.0084510
pmid:24367669
pmcid:PMC3867515
fatcat:jncg46hgi5bcdohjnrdosdg2ay
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... o optimal combinations to maximize the different coefficients, namely, MCC, accuracy and recall, to measure the screening performance. Various factors that influence filtering efficiency, including clustering methods, the composition of test sets (random, the most diverse and cluster population-dependent) and hit mode (the compound must fit at least one or two models from a final combination) were investigated. This method outmatched both single hypothesis and random linear combination approaches.
Constrained clustering with a complex cluster structure
2016
Advances in Data Analysis and Classification
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We are also thankful to Dawid Warszycki for providing access to the cheminformatics data. ...
Fourth column shows which groups of the lowest level of the hierarchy (Fig. 9 ) are merged to obtain reference partitions 1999;Śmieja and Warszycki 2016). ...
Fig. 9 Hierarchical structure of reference partition (Warszycki et al. 2013) • Apart from that, the proposed algorithm detects quite precisely the right number of regions. ...
doi:10.1007/s11634-016-0254-x
fatcat:eqtrgzcyw5datgxuiyapdrusui
11th German Conference on Chemoinformatics (GCC 2015)
2016
Journal of Cheminformatics
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