Average information content maximization : a new approach for fingerprint hybridization and reduction

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 time-consuming. In this study, we present a new method of hybrid reduced fingerprint construction, the Average Information Content Maximization 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-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6), 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

Pharmacoprint -- a combination of pharmacophore fingerprint and artificial intelligence as a tool for computer-aided drug design

Structural fingerprints and pharmacophore modeling are methodologies that have been used for at least two decades in various fields of cheminformatics: from similarity searching to machine learning (ML). Advances in silico techniques consequently led to combining both these methodologies into a new approach known as pharmacophore fingerprint. Herein, we propose a high-resolution, pharmacophore fingerprint called Pharmacoprint that encodes the presence, types, and relationships between pharmacophore features of a molecule. Pharmacoprint was evaluated in classification experiments by using ML algorithms (logistic regression, support vector machines, linear support vector machines, and neural networks) and outperformed other popular molecular fingerprints (i.e., Estate, MACCS, PubChem, Substructure, Klekotha-Roth, CDK, Extended, and GraphOnly) and ChemAxon Pharmacophoric Features fingerprint. Pharmacoprint consisted of 39973 bits; several methods were applied for dimensionality reduction, and the best algorithm not only reduced the length of bit string but also improved the efficiency of ML tests. Further optimization allowed us to define the best parameter settings for using Pharmacoprint in discrimination tests and for maximizing statistical parameters. Finally, Pharmacoprint generated for 3D structures with defined hydrogens as input data was applied to neural networks with a supervised autoencoder for selecting the most important bits and allowed to maximize Matthews Correlation Coefficient up to 0.962. The results show the potential of Pharmacoprint as a new, perspective tool for computer-aided drug design.Comment: Journal of Chemical Information and Modeling (2021

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

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 dibenzo[b,f]azocin-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

Development of advocacy in Czechoslovakia 1918 - 1989

Development of advocacy in Czechoslovakia 1918-1989 The thesis described and analysed the historical development of advocacy on the territory of Czechoslovakia from 1918 to 1989. It took into account the previous historical period, thus the beginnings of advocacy in Roman law, the legal profession in our country till 1848 and the historical phase between 1848 and 1918, very important for Czechoslovakia, when the basic legal regulations were created which were first accepted by independent Czechoslovakia in an unchanged form and were modified over time. Along with the law of the Roman Empire, the Austria-Hungary law was crucial for the formation of the cornerstones of today's modern advocacy. The thesis also covered chapters that included the definition of basic and associated terms that relate to advocacy, and last but not least a description of the current legislation of advocacy as well. The base of the thesis was represented by a historic period since the establishment of independent Czechoslovakia, through the second Czech-Slovak Republic, the Protectorate of Bohemia and Moravia, the short period after liberation and the communist regime from 1948 until after the revolutionary year of 1989, which, for the Czech advocacy, featured a return to democratic roots and First Republic's traditions of..

Classification times.

<p>Mean training times of a random forest classifier for various fingerprint representations averaged over all data sets of active and inactive compounds.</p

Exemplary hashed (A) and non-hashed (B) fingerprints.

<p>Presence of “1” and “0” corresponds to presence or absence of a particular pattern, repectively. In case of hashed fingerprint (A) bit collision phenomena is presented—one bit encodes more than one motif.</p