RNA mA methyltransferase activator affects anxiety-related behaviours, monoamines and striatal gene expression in the rat.

Modification of mRNA by methylation is involved in post-transcriptional regulation of gene expression by affecting the splicing, transport, stability and translation of mRNA. Methylation of adenosine at N (mA) is one of the most common and important cellular modification occurring in the mRNA of eukaryotes. Evidence that mA mRNA methylation is involved in regulation of stress response and that its dysregulation may contribute to the pathogenesis of neuropsychiatric disorders is accumulating.

Epitranscriptomic regulation in fasting hearts: implications for cardiac health.

Cardiac tolerance to ischaemia can be increased by dietary interventions such as fasting, which is associated with significant changes in myocardial gene expression. Among the possible mechanisms of how gene expression may be altered are epigenetic modifications of RNA - epitranscriptomics. N-methyladenosine (mA) and N,2'-O-dimethyladenosine (mAm) are two of the most prevalent modifications in mRNA.

The structure and function of YTHDF epitranscriptomic mA readers.

Specific RNA sequences modified by a methylated adenosine, N-methyladenosine (mA), contribute to the post-transcriptional regulation of gene expression. The quantity of mA in RNA is orchestrated by enzymes that write and erase it, while its effects are mediated by proteins that bind to read this modification. Dysfunction of this post-transcriptional regulatory process has been linked to human disease.

MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α.

The Impact of Software Used and the Type of Target Protein on Molecular Docking Accuracy.

The modern development of computer technology and different in silico methods have had an increasing impact on the discovery and development of new drugs. Different molecular docking techniques most widely used in silico methods in drug discovery. Currently, the time and financial costs for the initial hit identification can be significantly reduced due to the ability to perform high-throughput virtual screening of large compound libraries in a short time.

Epitranscriptomics of Ischemic Heart Disease-The IHD-EPITRAN Study Design and Objectives.

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination.

HIV Replication Is Increased by RNA Methylation METTL3/METTL14/WTAP Complex Activators.

The N6-methyladenosine (mA) modifications in both viral and host cell RNAs play an important role in HIV-1 virus genome transcription and virus replication. We demonstrate here that activators of the METTL3/METTL14/WTAP RNA methyltransferase complex enhance the production of virus particles in cells harboring HIV-1 provirus. In parallel, the amount of mA residues in the host cell mRNA was increased in the presence of these activator compounds.

Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors.

The RNA 6-N-methyladenosine (m6A) demethylase ALKBH5 has been shown to be oncogenic in several cancer types, including leukemia and glioblastoma. We present here the target-tailored development and first evaluation of the antiproliferative effects of new ALKBH5 inhibitors. Two compounds, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid (3) and 4-{[(furan-2-yl)methyl]amino}-1,2-diazinane-3,6-dione (6), with IC values of 0.

Novel Analogues of the Chikungunya Virus Protease Inhibitor: Molecular Design, Synthesis, and Biological Evaluation.

The Chikungunya virus (CHIKV) is an arbovirus belonging to the genus of the family. CHIKV is transmitted by the mosquitoes and causes Chikungunya fever. CHIKV outbreaks have occurred in Africa, Asia, Europe, and the countries of Indian and Pacific Oceans.

Small-Molecule Inhibitors of the RNA M6A Demethylases FTO Potently Support the Survival of Dopamine Neurons.

The fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, is an important regulator of central nervous system development, neuronal signaling and disease. We present here the target-tailored development and biological characterization of small-molecule inhibitors of FTO. The active compounds were identified using high-throughput molecular docking and molecular dynamics screening of the ZINC compound library.

1,3-Thiazolbenzamide Derivatives as Chikungunya Virus nsP2 Protease Inhibitors.

Chikungunya fever results from an infection with Chikungunya virus (CHIKV, genus ) that is prevalent in tropical regions and is spreading fast to temperate climates with documented outbreaks in Europe and the Americas. Currently, there are no available vaccines or antiviral drugs for prevention or treatment of Chikungunya fever. The nonstructural proteins (nsPs) of CHIKV responsible for virus replication are promising targets for the development of new antivirals.

Novel RET agonist for the treatment of experimental neuropathies.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) alleviate symptoms of experimental neuropathy, protect and stimulate regeneration of sensory neurons in animal models of neuropathic pain, and restore their functional activity. However, clinical development of GFL proteins is complicated by their poor pharmacokinetic properties and multiple effects mediated by several receptors. Previously, we have identified a small molecule that selectively activates the major signal transduction unit of the GFL receptor complex, receptor tyrosine kinase RET, as an alternative to GFLs, for the treatment of neuropathic pain.

Multitarget Approach to Drug Candidates against Alzheimer's Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets.

Alzheimer's disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer's disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets.

Glial cell line-derived neurotrophic factor receptor Rearranged during transfection agonist supports dopamine neurons in Vitro and enhances dopamine release In Vivo.

Background: Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration.

Discovery of Small Molecules that Activate RNA Methylation through Cooperative Binding to the METTL3-14-WTAP Complex Active Site.

Chemical modifications of RNA provide an additional, epitranscriptomic, level of control over cellular functions. N-6-methylated adenosines (m6As) are found in several types of RNA, and their amounts are regulated by methyltransferases and demethylases. One of the most important enzymes catalyzing generation of m6A on mRNA is the trimer N-6-methyltransferase METTL3-14-WTAP complex.

Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) support the survival and functioning of various neuronal populations. Thus, they could be attractive therapeutic agents against a multitude of neurodegenerative diseases caused by progressive death of GFLs responsive neurons. Small-molecule ligands BT13 and BT18 show an effect on GDNF family receptor GFRα1 and RET receptor tyrosine kinase RetA function.

Identification of Natural Compounds against Neurodegenerative Diseases Using In Silico Techniques.

The aim of this study was to identify new potentially active compounds for three protein targets, tropomyosin receptor kinase A (TrkA), -methyl-d-aspartate (NMDA) receptor, and leucine-rich repeat kinase 2 (LRRK2), that are related to various neurodegenerative diseases such as Alzheimer's, Parkinson's, and neuropathic pain. We used a combination of machine learning methods including artificial neural networks and advanced multilinear techniques to develop quantitative structure⁻activity relationship (QSAR) models for all target proteins. The models were applied to screen more than 13,000 natural compounds from a public database to identify active molecules.

Small-Molecule Ligands as Potential GDNF Family Receptor Agonists.

To find out potential GDNF family receptor α1 (GFRα1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRα1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity ≥ 80%).

A Novel Small Molecule GDNF Receptor RET Agonist, BT13, Promotes Neurite Growth from Sensory Neurons and Attenuates Experimental Neuropathy in the Rat.

Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage.

Design and Validation of Novel Chikungunya Virus Protease Inhibitors.

Chikungunya virus (CHIKV; genus Alphavirus) is the causative agent of chikungunya fever. CHIKV replication can be inhibited by some broad-spectrum antiviral compounds; in contrast, there is very little information about compounds specifically inhibiting the enzymatic activities of CHIKV replication proteins. These proteins are translated in the form of a nonstructural (ns) P1234 polyprotein precursor from the CHIKV positive-strand RNA genome.

Indole-like Trk receptor antagonists.

The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR.

Have artificial neural networks met expectations in drug discovery as implemented in QSAR framework?

Introduction: Artificial neural networks (ANNs) are highly adaptive nonlinear optimization algorithms that have been applied in many diverse scientific endeavors, ranging from economics, engineering, physics, and chemistry to medical science. Notably, in the past two decades, ANNs have been used widely in the process of drug discovery.

Areas Covered: In this review, the authors discuss advantages and disadvantages of ANNs in drug discovery as incorporated into the quantitative structure-activity relationships (QSAR) framework.

Robust Modeling and Scaffold Hopping: Case Study Based on HIV Reverse Transcriptase Inhibitors Type-1 Data.

Background: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of AIDS occurs across mucosal surfaces or by direct inoculation.

Objective: The objective of this study was to consider chemically diverse scaffold sets of HIV-1 Reverse Transcriptase Inhibitors (HIV-1 RTI) subjected to ideal oriented QSAR with large descriptor space.

Method: We generated a four-parameter QSAR model based on 111 data points, which provided an optimum prediction of HIV-1 RTI for overall 367 experimentally measured compounds.

Prediction of Cell-Penetrating Peptides.

The in silico methods for the prediction of the cell-penetrating peptides are reviewed. Those include the multivariate statistical methods, machine-learning methods such as the artificial neural networks and support vector machines, and molecular modeling techniques including molecular docking and molecular dynamics.The applicability of the methods is demonstrated on the basis of the exemplary cases from the literature.