A5060640473- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Chemical Synthesis and Analysis
- Crystallography and molecular interactions
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Click Chemistry and Applications
- Neurotransmitter Receptor Influence on Behavior
- Phenothiazines and Benzothiazines Synthesis and Activities
- Neuroscience and Neuropharmacology Research
- Synthesis and Characterization of Heterocyclic Compounds
- Metabolomics and Mass Spectrometry Studies
- Pharmacological Receptor Mechanisms and Effects
- Spectroscopy and Chemometric Analyses
- Fluorine in Organic Chemistry
- Analytical Chemistry and Chromatography
- Synthesis and biological activity
- Machine Learning in Materials Science
- Protein Structure and Dynamics
- Chemical Reaction Mechanisms
- Nicotinic Acetylcholine Receptors Study
- Synthesis and Reactivity of Heterocycles
- Molecular Spectroscopy and Structure
- Neuropeptides and Animal Physiology
Akademia Tarnowska
2016-2025
Polish Academy of Sciences
2015-2024
Maj Institute of Pharmacology
2015-2024
Polish Academy of Learning
2018-2024
Institute of Pharmacology
2015-2022
Medicina
2011-2019
Cracow University of Technology
2018
Jagiellonian University
2009-2010
We have analyzed hydrogen bonding in a number of species, containing from two to four bonds. The examples were chosen such way that they would enable us examine three different bonds involving OH-O, NH-O, and NH-N. A common feature the investigated systems is all are expected exhibit resonance assisted (RAHB) electronic pi-framework. Our analysis was based on recently developed method combines extended transition state scheme with theory natural orbitals for chemical valence (ETS-NOCV). find...
Although the salt bridge is strongest among all known noncovalent molecular interactions, no comprehensive studies have been conducted to date examine its role and significance in drug design. Thus, a systematic study of biological systems reported herein, with broad analysis publicly available data from Protein Data Bank, DrugBank, ChEMBL, GPCRdb. The results revealed distance angular preferences as well privileged motifs bridges ligand–receptor complexes, which could be used design...
Abstract Background The paper presents a thorough analysis of the influence number negative training examples on performance machine learning methods. Results impact this rather neglected aspect methods application was examined for sets containing fixed positive and varying randomly selected from ZINC database. An increase in ratio to instances found greatly most investigated evaluating parameters ML simulated virtual screening experiments. In majority cases, substantial increases precision...
Fluorine is a common substituent in medicinal chemistry and found up to 50% of the most profitable drugs. In this study, statistical analysis nature, geometry, frequency hydrogen bonds (HBs) formed between aromatic aliphatic C-F groups small molecules biological targets Protein Data Bank (PDB) repository was presented. Interaction energies were calculated for those complexes using three different approaches. The obtained results indicated that interaction energy F-containing HBs determined...
This study presents a novel approach to 1H NMR-based machine learning (ML) models for predicting logD using computer-generated NMR spectra. Building on our previous work, which integrated experimental data, this addresses key limitations associated with measurements, such as sample stability, solvent variability, and extensive processing, by replacing them fully computational workflows. Benchmarking across various density functional theory (DFT) functionals basis sets highlighted their...
A virtual screening campaign aimed at finding structurally new compounds active 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, Ki = 91 nM), was selected as hit for further optimization. As expected, the chemical scaffold compound significantly different from all serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, 43 representing...
Abstract Background A growing popularity of machine learning methods application in virtual screening, both classification and regression tasks, can be observed the past few years. However, their effectiveness is strongly dependent on many different factors. Results In this study, influence way forming set inactives process was examined: random diverse selection from ZINC database, MDDR database libraries generated according to DUD methodology. All were tested two modes: using one test set,...
A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in 5-HT7R as case study. The procedure identified two sets hot spots, extracellular (D2.65, T2.64, E7.35) transmembrane (C3.36, T5.39, S5.42), which were further verified synthesized...
Alzheimer's disease is becoming a growing problem increasing at tremendous rate. Serotonin 5-HT6 receptors appear to be particularly attractive target from therapeutic perspective, due their involvement not only in cognitive processes, but also depression and psychosis. In this work, we present the synthesis broad biological characterization of new series 18 compounds with unique 1,3,5-triazine backbone, as potent receptor ligands. The main aim research compare activity newly synthesized...
The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 3 receptors (5-HT-Rs) monoamine oxidase B (MAO-B) as an approach treating AD. key structural features required MAO-B inhibition 5-HT6R antagonism interaction with 5-HT3R were determined using molecular dynamic simulations cryo-electron microscopy, respectively. Bioavailable PZ-1922...
The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists antagonists appears to be clinically relevant. mechanism of binding (R) varies. In present study, we conducted an in-depth computational teasing out key similarities differences modes, complex dynamics, energies D4R antagonists. dynamic network method was applied investigate communication paths between ligand (L) G-protein site (GBS) human D4R. Finally, fragment...
A novel approach to the utilization of nuclear magnetic resonance (NMR) spectroscopy data in prediction logD through machine learning algorithms is shown. In analysis, a set 754 chemical compounds, organized into 30 clusters, was evaluated using advanced models, such as Support Vector Regression (SVR), Gradient Boosting, and AdaBoost, comprehensive validation testing methods were employed, including 10-fold cross-validation, bootstrapping, leave-one-out. The study revealed superior...
The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) plays an essential role in the termination of serotonergic neurotransmission by removing 5-HT from synaptic cleft into presynaptic neuron. It is also pharmacological importance being targeted antidepressants and psychostimulant drugs. Here, five commercial databases containing approximately 3.24 million drug-like compounds have been screened using a combination two-dimensional (2D) fingerprint-based three-dimensional (3D)...
The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries protein–ligand complexes halogen bonding. procedure involves quantum-polarized ligand (QPLD) obtain QM-derived atomic charges in protein environment at B3PW91/cc-pVTZ level and MM/GBSA (generalized-Born/surface area) algorithm calculate free energies resultant complexes. performance validated using a set 106...
In light of the multifactorial origin neurodegenerative disorders and some body evidence indicating that pharmacological blockade serotonin 5-HT6 dopamine D3 receptors might be beneficial for cognitive decline, we envisioned (S)-1-[(3-chlorophenyl)sulfonyl]-4-(pyrrolidine-3-yl-amino)-1H-pyrrolo[3,2-c]quinoline (CPPQ), a neutral antagonist 5-HT6R, as chemical template designing dual antagonists 5-HT6/D3 receptors. As shown by in vitro experiments, supported quantum calculations molecular...
Structural fingerprints and pharmacophore modeling are methodologies that have been used for at least 2 decades in various fields of cheminformatics, from similarity searching to machine learning (ML). Advances silico techniques consequently led combining both these into a new approach known as the fingerprint. Herein, we propose high-resolution, fingerprint called Pharmacoprint encodes presence, types, relationships between features molecule. was evaluated classification experiments by...
G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active which depend on the nature bound ligand. In consequence, states can initiate specific signal transduction pathways. The study identified compound 7e, acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT6R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted changes for 7e inverse agonist PZ-1444....