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Bioisosteric Matrices for Ligands of Serotonin Receptors

Dawid Warszycki, Stefan Mordalski, Jakub Staroń, Andrzej J. Bojarski
2015 ChemMedChem  
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

Linn Evenseth, Dawid Warszycki, Andrzej Bojarski, Mari Gabrielsen, Ingebrigt Sylte
2019 Molecules  
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
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.
doi:10.3390/molecules24050935 fatcat:fvp2k6ddzvgt7eibhtprra7yga

Average Information Content Maximization—A New Approach for Fingerprint Hybridization and Reduction

Marek Śmieja, Dawid Warszycki, Paul Taylor
2016 PLoS ONE  
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
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.
doi:10.1371/journal.pone.0146666 pmid:26784447 pmcid:PMC4718645 fatcat:r4yc3hkgsrbgzay72pnttve3uy

Asymmetric Clustering Index in a Case Study of 5-HT1A Receptor Ligands

Marek Śmieja, Dawid Warszycki, Jacek Tabor, Andrzej J. Bojarski, Matthias Dehmer
2014 PLoS ONE  
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

Thibaud Freyd, Dawid Warszycki, Stefan Mordalski, Andrzej J. Bojarski, Ingebrigt Sylte, Mari Gabrielsen, Alessio Lodola
2017 PLoS ONE  
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

Jakub Staroń, Dawid Warszycki, Justyna Kalinowska-Tłuścik, Grzegorz Satała, Andrzej J. Bojarski
2015 RSC Advances  
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

Jakub Staroń, Stefan Mordalski, Dawid Warszycki, Grzegorz Satała, Adam Hogendorf, Andrzej J. Bojarski
2017 ACS Medicinal Chemistry Letters  
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

Dawid Warszycki, Marek Śmieja, Rafał Kafel
2017 Molecular diversity  
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
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.
doi:10.1007/s11030-017-9729-8 pmid:28185036 pmcid:PMC5438429 fatcat:eqks3xtyynesjerc64aphqlwwm

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

Bartosz Bieszczad, Damian Garbicz, Marta Świtalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elżbieta Grzesiuk, Adam Mieczkowski
2021 Pharmaceuticals  
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
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.
doi:10.3390/ph14090851 pmid:34577551 fatcat:m3kwxeefn5eqlkoyujxvic5tma

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

Justyna Kalinowska-Tłuścik, Jakub Staroń, Anna Krawczuk, Stefan Mordalski, Dawid Warszycki, Grzegorz Satała, Adam S. Hogendorf, Andrzej J. Bojarski
2018 RSC Advances  
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

Dawid Warszycki, Stefan Mordalski, Kurt Kristiansen, Rafał Kafel, Ingebrigt Sylte, Zdzisław Chilmonczyk, Andrzej J. Bojarski, Andrea Cavalli
2013 PLoS ONE  
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
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.
doi:10.1371/journal.pone.0084510 pmid:24367669 pmcid:PMC3867515 fatcat:jncg46hgi5bcdohjnrdosdg2ay

Constrained clustering with a complex cluster structure

Marek Śmieja, Magdalena Wiercioch
2016 Advances in Data Analysis and Classification  
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)

Uli Fechner, Chris de Graaf, Andrew E. Torda, Stefan Güssregen, Andreas Evers, Hans Matter, Gerhard Hessler, Nicola J. Richmond, Peter Schmidtke, Marwin H. S. Segler, Mark P. Waller, Stefanie Pleik (+248 others)
2016 Journal of Cheminformatics  
doi:10.1186/s13321-016-0119-5 pmid:29270804 pmcid:PMC4896257 fatcat:akoqbbe6fvc5bgc6qwnxqhiaya