A5072327557- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Monoclonal and Polyclonal Antibodies Research
- Neuroscience and Neuropharmacology Research
- Click Chemistry and Applications
- Pharmacogenetics and Drug Metabolism
- Analytical Chemistry and Chromatography
- Synthesis and Biological Evaluation
- Nicotinic Acetylcholine Receptors Study
- Evolutionary Game Theory and Cooperation
- Origins and Evolution of Life
- Gene Regulatory Network Analysis
- Neurotransmitter Receptor Influence on Behavior
- Phenothiazines and Benzothiazines Synthesis and Activities
- Chemical Reaction Mechanisms
- Synthesis and Reactivity of Heterocycles
- bioluminescence and chemiluminescence research
- Evolution and Genetic Dynamics
- Steroid Chemistry and Biochemistry
- Chemokine receptors and signaling
- Advanced Biosensing Techniques and Applications
Maj Institute of Pharmacology
2013-2023
Polish Academy of Sciences
2013-2023
University of Copenhagen
2020
Institute of Pharmacology
2018
Medicina
2011-2017
Jagiellonian University
2014
Recent developments in G protein-coupled receptor (GPCR) structural biology and pharmacology have greatly enhanced our knowledge of structure-function relations, helped improve the scientific foundation for drug design studies. The GPCR database, GPCRdb, serves a dual role disseminating enabling new by providing reference data, analysis tools interactive diagrams. This paper highlights features fifth major GPCRdb release: (i) crystal structure browsing, superposition display ligand...
G protein-coupled receptors are the most abundant mediators of both human signalling processes and therapeutic effects. Herein, we report GPCRome-wide homology models unprecedented quality, roughly 150 000 GPCR ligands with data on biological activities commercial availability. Based strategy 'Less model - more Xtal', each exploits a main template alternative local templates. This achieved higher similarity to new structures than any existing resources, refined crystal missing or distorted...
G protein-coupled receptors (GPCRs) form both the largest family of membrane proteins and drug targets, mediating action one-third medicines. The GPCR database, GPCRdb serves >4 000 researchers every month offers reference data, analysis own or literature experiment design dissemination published datasets. Here, we describe new updated resources with a particular focus on integration sequence, structure function. contains all human non-olfactory GPCRs (and >27 orthologs), G-proteins...
Homology modeling is a reliable method of predicting the three-dimensional structures proteins that lack NMR or X-ray crystallographic data. It employs assumption structural resemblance exists between closely related proteins. Despite availability many crystal possible templates, only closest ones are chosen for homology purposes. To validate aforementioned approach, we performed four serotonin receptors (5-HT1AR, 5-HT2AR, 5-HT6R, 5-HT7R) virtual screening purposes, using 10 available...
Docking is one of the most important steps in virtual screening pipelines, and it an established method for examining potential interactions between ligands receptors. However, this computationally expensive, often among last process compound libraries evaluation. In work, we investigate feasibility learning a deep neural network to predict docking output directly from two-dimensional structure. The developed protocol orders magnitude faster than typical software, returns ligand-receptor...
This study explores a new approach to pharmacophore screening involving the use of an optimized linear combination models instead single hypothesis. The implementation and evaluation developed methodology are performed for complete known chemical space 5-HT1AR ligands (3616 active compounds with Ki < 100 nM) acquired from ChEMBL database. Clusters generated three different methods were basis individual hypotheses, which assembled into optimal combinations maximize coefficients, namely, MCC,...
G protein-coupled receptors (GPCRs) are intensively studied due to their therapeutic potential as drug targets. Members of this large family transmembrane receptor proteins mediate signal transduction in diverse cell types and play key roles human physiology health. In 2013 the research consortium GLISTEN (COST Action CM1207) was founded with goal harnessing substantial growth knowledge GPCR structure dynamics push forward development molecular modulators function. The success GLISTEN,...
γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in central nervous system, and disturbances GABAergic system have been implicated numerous neurological neuropsychiatric diseases. The GABAB receptor a heterodimeric class C G protein-coupled (GPCR) consisting of GABAB1a/b GABAB2 subunits. Two ligand binding sites described, namely orthosteric GABA site located extracellular GABAB1 Venus fly trap domain allosteric found transmembrane domain. To date, only experimentally...
Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to X-ray crystallography community. This lack direct structural information not only hampers our knowledge regarding binding modes many popular ligands (including endogenous neurotransmitter-serotonin), but also limits search for more potent compounds. In this paper we shed new light on 3D pharmacological properties 5-HT1A by using a ligand-guided approach (ALiBERO) grounded...
Distinguishing active from inactive compounds is one of the crucial problems molecular docking, especially in context virtual screening experiments. The randomization poses and natural flexibility protein make this discrimination even harder. Some recent approaches to post-docking analysis use an ensemble receptor models mimic naturally occurring conformational diversity. However, optimal number conformations yet be determined. In study, we compare results a retrospective beta-2 adrenergic...
The development of compounds with enhanced activity and selectivity by a conserved spatial orientation the pharmacophore elements has long history in medicinal chemistry. Rigidified are an example this concept. However, intramolecular interactions were seldom used as basis for conformational restraints. Here, we show weak that contribute to relatively well-conserved geometry N1-arylsulfonyl indole derivatives. structure analysis along quantum mechanics calculations revealed crucial impact...
Molecular docking, despite its undeniable usefulness in computer-aided drug design protocols and the increasing sophistication of tools used prediction ligand–protein interaction energies, is still connected with a problem effective results analysis. In this study, novel protocol for automatic evaluation numerous docking presented, being combination Structural Interaction Fingerprints Spectrophores descriptors, machine-learning techniques, multi-step Such an approach takes into consideration...
In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through tandem bioisostere generation/virtual screening protocol in search 5-HT6R ligands. The discovered resulted design highly active basic and nonbasic ligands (5-HT6R Ki = 1 nM for compound 6b 4 its neutral analog 7b). Additionally, molecular modeling suggested that hydroxyl group 7a–7d forms hydrogen bonds with aspartic acid D3×32 or D7.36×35.
Abstract The concept of bioisosteric replacement matrices is applied to explore the chemical space serotonin receptor ligands, aiming determine most efficient ways manipulating affinity for all 5‐HT subtypes. Analysis a collection over 1 million bioisosteres compounds with measured activity towards receptors revealed that an average 31 % ligands each target are mutual bioisosteres. In addition, collected dataset allowed development matrices—qualitative and quantitative descriptions...