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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
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 drugdoi:10.3390/molecules24050935 fatcat:fvp2k6ddzvgt7eibhtprra7yga
more »... 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.
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 Contentdoi:10.1371/journal.pone.0146666 pmid:26784447 pmcid:PMC4718645 fatcat:r4yc3hkgsrbgzay72pnttve3uy
more »... 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.
These indices were evaluated based on the reference reported by Warszycki et al. ... As a reference, the manually constructed partition of Warszycki  was utilized. ...doi:10.1371/journal.pone.0102069 pmid:25019251 pmcid:PMC4096758 fatcat:lbn2h35ixrdhpo4qj6y5yfqvhm
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
A bioisosteric strategy was successfully implemented with a screening protocol for new, potent 5-HT6R ligands.doi:10.1039/c5ra00054h fatcat:jrw34yc7azbx5eqnkhqkdrloga
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
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-learningdoi:10.1007/s11030-017-9729-8 pmid:28185036 pmcid:PMC5438429 fatcat:eqks3xtyynesjerc64aphqlwwm
more »... 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.
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 ondoi:10.3390/ph14090851 pmid:34577551 fatcat:m3kwxeefn5eqlkoyujxvic5tma
more »... -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 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
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 assembleddoi:10.1371/journal.pone.0084510 pmid:24367669 pmcid:PMC3867515 fatcat:jncg46hgi5bcdohjnrdosdg2ay
more »... 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.
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