Sampling and Scoring in Protein-Protein Docking.

Protein-protein docking is considered one of the most important techniques supporting experimental proteomics. Recent developments in the field of computer science helped to improve this computational technique so that it better handles the complexity of protein nature. Sampling algorithms are responsible for the generation of numerous protein-protein ensembles.

Discovery and in vitro Evaluation of Novel Serotonin 5-HT Receptor Ligands Identified Through Virtual Screening.

The 5-HT receptor is a molecular target of high pharmacological importance. Ligands of this protein, particularly atypical antipsychotics, are useful in the treatment of numerous mental disorders, including schizophrenia and major depressive disorder. Structure-based virtual screening using a 5-HT receptor complex was performed to identify novel ligands for the 5-HT receptor, serving as potential antidepressants.

The Depressiveness, Quality of Life and NEO-FFI Scale in Patients with Selected Genodermatoses.

Dermatological conditions extend beyond physical symptoms, profoundly impacting the psychological well-being of patients. This study explores the intricate relationship between depressive symptoms, quality of life (QoL), and personality traits in individuals diagnosed with specific genodermatoses. The study cohort comprised 30 patients with genodermatoses treated at the dermatology clinic, and a healthy control group.

Novel 1-(1-Arylimiazolin-2-Yl)-3-Arylalkilurea Derivatives with Modulatory Activity on Opioid MOP Receptors.

μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties of the interactions of the MOP receptor (human mu opioid receptor, OP3) with ligands and specific intracellular signaling pathways allows for the designation of new directions of research with respect to compounds with analgesic effects in a mechanism different from classical ligands.

Caspases in Alzheimer's Disease: Mechanism of Activation, Role, and Potential Treatment.

With the aging of the population, treatment of conditions emerging in old age, such as neurodegenerative disorders, has become a major medical challenge. Of these, Alzheimer's disease, leading to cognitive dysfunction, is of particular interest. Neuronal loss plays an important role in the pathophysiology of this condition, and over the years, a great effort has been made to determine the role of various factors in this process.

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1-21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent.

The application of WaterMap-guided structure-based virtual screening in novel drug discovery.

Introduction: Nowadays, it is widely accepted that water molecules play a key role in binding a ligand to a molecular target. Neglecting water molecules in the process of molecular recognition was the result of several failures of the structure-based drug discovery campaigns. The application of WaterMap, in particular WaterMap-guided molecular docking, enables the reasonably accurate and quick description of the location and energetics of water molecules at the ligand-protein interface.

Effect of Commonly Used Cosmetic Preservatives on Healthy Human Skin Cells.

Cosmetic products contain preservatives to prevent microbial growth. The various types of preservatives present in skincare products applied on the skin induce many side effects. We tested several types of preservatives such as phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea (IU), the composition of gluconolactone and sodium benzoate (GSB), diazolidinyl urea (DU), and two grapefruit essential oils, one of which was industrially produced and a second which was freshly distilled from fresh grapefruit peels.

Illuminating the "Twilight Zone": Advances in Difficult Protein Modeling.

Homology modeling was long considered a method of choice in tertiary protein structure prediction. However, it used to provide models of acceptable quality only when templates with appreciable sequence identity with a target could be found. The threshold value was long assumed to be around 20-30%.

The Role of Genetics in the Development and Pharmacotherapy of Depression and Its Impact on Drug Discovery.

Complex disorders, such as depression, remain a mystery for scientists. Although genetic factors are considered important for the prediction of one's vulnerability, it is hard to estimate the exact risk for a patient to develop depression, based only on one category of vulnerability criteria. Genetic factors also regulate drug metabolism, and when they are identified in a specific combination, may result in increased drug resistance.

Modulation of the MOP Receptor (μ Opioid Receptor) by Imidazo[1,2-]imidazole-5,6-Diones: In Search of the Elucidation of the Mechanism of Action.

The μ-opioid receptors belong to the family of G protein-coupled receptors (GPCRs), and their activation triggers a cascade of intracellular relays with the final effect of analgesia. Classical agonists of this receptor, such as morphine, are the main targets in the treatment of both acute and chronic pain. However, the dangerous side effects, such as respiratory depression or addiction, significantly limit their widespread use.

What are the challenges with multi-targeted drug design for complex diseases?

Introduction: Current findings on multifactorial diseases with a complex pathomechanism confirm that multi-target drugs are more efficient ways in treating them as opposed to single-target drugs. However, to design multi-target ligands, a number of factors and challenges must be taken into account.

Areas Covered: In this perspective, we summarize the concept of application of multi-target drugs for the treatment of complex diseases such as neurodegenerative diseases, schizophrenia, diabetes, and cancer.

Experimental and Computational Structural Studies of 2,3,5-Trisubstituted and 1,2,3,5-Tetrasubstituted Indoles as Non-Competitive Antagonists of GluK1/GluK2 Receptors.

The blockade of kainate receptors, in particular with non-competitive antagonists, has-due to their anticonvulsant and neuroprotective properties-therapeutic potential in many central nervous system (CNS) diseases. Deciphering the structural properties of kainate receptor ligands is crucial to designing medicinal compounds that better fit the receptor binding pockets. In light of that fact, here, we report experimental and computational structural studies of four indole derivatives that are non-competitive antagonists of GluK1/GluK2 receptors.

Allosteric modulation of dopamine D receptor in complex with G and G proteins: the effect of subtle structural and stereochemical ligand modifications.

Background: Allosteric modulation of G protein-coupled receptors (GPCRs) is nowadays one of the hot topics in drug discovery. In particular, allosteric modulators of D receptor have been proposed as potential modern therapeutics to treat schizophrenia and Parkinson's disease.

Methods: To address some subtle structural and stereochemical aspects of allosteric modulation of D receptor, we performed extensive in silico studies of both enantiomers of two compounds (compound 1 and compound 2), and one of them (compound 2) was synthesized as a racemate in-house and studied in vitro.

Overcoming Depression with 5-HT Receptor Ligands.

Depression is a multifactorial disorder that affects millions of people worldwide, and none of the currently available therapeutics can completely cure it. Thus, there is a need for developing novel, potent, and safer agents. Recent medicinal chemistry findings on the structure and function of the serotonin 2A (5-HT) receptor facilitated design and discovery of novel compounds with antidepressant action.

Current Approaches and Tools Used in Drug Development against Parkinson's Disease.

Parkinson's disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease.

The Antipsychotic D2AAK1 as a Memory Enhancer for Treatment of Mental and Neurodegenerative Diseases.

The treatment of memory impairments associated with the central nervous system diseases remains an unmet medical need with social and economic implications. Here we show, that a multi-target ligand of aminergic G protein-coupled receptors with antipsychotic activity in vivo (D2AAK1) stimulates neuron growth and survival and promotes neuron integrity. We focused on the multilevel evaluation of the D2AAK1-related effects on neurons in terms of behavioral, cellular, molecular, and biochemical features in vivo and in vitro, such as memory-related responses, locomotor activity, tissue sections analysis, metabolic activity, proliferation level, neurons morphology, and proteins level involved in intracellular signaling pathways.

Novel Positive Allosteric Modulators of µ Opioid Receptor-Insight from In Silico and In Vivo Studies.

Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation.

Tuning Down the Pain - An Overview of Allosteric Modulation of Opioid Receptors: Mechanisms of Modulation, Allosteric Sites, Modulator Syntheses.

Opioid signaling plays a central role in pain perception. As such, it remains the main target in the development of antinociceptive agents, despite serious side effects involved. In recent years, hopes for improved opioid painkillers are rising, together with our understanding of allosterism and biased signaling mechanisms.

Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Maintenance Association between Environmental Cues and Rewarding Properties of Ethanol in Rats.

Metabotropic glutamate subtype 5 (mGlu5) receptors are implicated in various forms of synaptic plasticity, including drugs of abuse. In drug-addicted individuals, associative memories can drive relapse to drug use. The present study investigated the potential of the mGlu5 receptor positive allosteric modulator (PAM), VU-29 (30 mg/kg, i.

Toxicity of Carlina Oxide-A Natural Polyacetylene from the Roots-In Vitro and In Vivo Study.

There are several reports indicating that the roots of the L. used to be commonly applied as a treatment measure in skin diseases and as an antiparasitic agent, starting from antiquity to the 19th century; however, nowadays, it has lost its importance. Currently, numerous studies are being conducted assessing the possibility of reintroducing -derived extracts to phytotherapy.

The effect of statins on psoriasis severity: a meta-analysis of randomized clinical trials.

Introduction: Statins may reduce the severity of psoriasis, but the available evidence is unclear. We conducted a meta-analysis of randomized controlled studies (RCTs) that investigated the effect of statins on psoriasis severity assessed with the Psoriasis Area and Severity Index (PASI).

Material And Methods: Two investigators searched independently the following databases: Medline, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.

Preferential Coupling of Dopamine D and D Receptor Isoforms with G and G Proteins-In Silico Study.

The dopamine D receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson's disease. Here, computational methods were used to construct the full models of the dopamine D receptor short (D) and long (D) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with G and G proteins. It was found that the D isoform preferentially couples with the G protein and D isoform with the G protein, which is in accordance with experimental data.

The Universal 3D QSAR Model for Dopamine D Receptor Antagonists.

In order to search for novel antipsychotics acting through the D receptor, it is necessary to know the structure-activity relationships for dopamine D receptor antagonists. In this context, we constructed the universal three-dimensional quantitative structure-activity relationship (3D- QSAR) model for competitive dopamine D receptor antagonists. We took 176 compounds from chemically different groups characterized by the half maximal inhibitory concentration (IC)from the CHEMBL database and docked them to the X-ray structure of the human D receptor in the inactive state.