Substituted Furanocoumarins as Novel Class of Antibacterial Translation Inhibitors.

Introduction: A variety of organic compounds has been reported to have antibacterial activity. However, antimicrobial resistance is one of the main problems of current anti-infective therapy, and the development of novel antibacterials is one of the main challenges of current drug discovery.

Methods: Using our previously developed dual-reporter High-Throughput Screening (HTS) platform, we identified a series of furanocoumarins as having high antibacterial activity.

Identification of Novel Antibacterials Using Machine Learning Techniques.

Many pharmaceutical companies are avoiding the development of novel antibacterials due to a range of rational reasons and the high risk of failure. However, there is an urgent need for novel antibiotics especially against resistant bacterial strains. Available models suffer from many drawbacks and, therefore, are not applicable for scoring novel molecules with high structural diversity by their antibacterial potency.

Deep learning enables rapid identification of potent DDR1 kinase inhibitors.

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days.

2-Pyrazol-1-yl-thiazole derivatives as novel highly potent antibacterials.

The present report describes our efforts to identify new structural classes of compounds having promising antibacterial activity using previously published double-reporter system pDualrep2. This semi-automated high-throughput screening (HTS) platform has been applied to perform a large-scale screen of a diverse small-molecule compound library. We have selected a set of more than 125,000 molecules and evaluated them for their antibacterial activity.

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents.

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g.

Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform.

Aim And Objective: Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity.

Identification of pyrrolo-pyridine derivatives as novel class of antibacterials.

A series of 5-oxo-4H-pyrrolo[3,2-b]pyridine derivatives was identified as novel class of highly potent antibacterial agents during an extensive large-scale high-throughput screening (HTS) program utilizing a unique double-reporter system-pDualrep2. The construction of the reporter system allows us to perform visual inspection of the underlying mechanism of action due to two genes-Katushka2S and RFP-which encode the proteins with different imaging signatures. Antibacterial activity of the compounds was evaluated during the initial HTS round and subsequent rescreen procedure.

AVN-322 is a Safe Orally Bio-Available Potent and Highly Selective Antagonist of 5-HT6R with Demonstrated Ability to Improve Impaired Memory in Animal Models.

Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer's disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD.

Identification of Novel Small-Molecule ASGP-R Ligands.

During the past decade asialoglycoprotein receptor (ASGP-R) expressed predominantly by hepatocytes has attracted a considerable attention as a convenient biomolecular trap for targeted drug delivery. Currently, several selective galactose-containing ligands equipped by drug molecules, e.g.

Small-molecule PSMA ligands. Current state, SAR and perspectives.

Prostate cancer (PC) is the prevalent malignancy widespread among men in the Western World. Prostate specific membrane antigen (PSMA) is an established PC marker and has been considered as a promising biological target for anti-PC drug delivery and diagnostics. The protein was found to be overexpressed in PC cells, including metastatic, and the neovasculature of solid tumors.

Synthesis, isomerization and biological activity of novel 2-selenohydantoin derivatives.

A set of novel selenohydantoins were synthesized via a convenient and versatile approach involving the reaction of isoselenocyanates with various amines. We also revealed an unexpected Z→E isomerization of pyridin-2-yl-substituted selenohydantoins in the presence of Cu(2+) cations. The detailed mechanism of this transformation was suggested on the basis of quantum-chemical calculations, and the key role of Cu(2+) was elucidated.

Computational insight into the chemical space of plant growth regulators.

An enormous technological progress has resulted in an explosive growth in the amount of biological and chemical data that is typically multivariate and tangled in structure. Therefore, several computational approaches have mainly focused on dimensionality reduction and convenient representation of high-dimensional datasets to elucidate the relationships between the observed activity (or effect) and calculated parameters commonly expressed in terms of molecular descriptors. We have collected the experimental data available in patent and scientific publications as well as specific databases for various agrochemicals.

A Comprehensive Insight into the Chemical Space and ADME Features of Small Molecule NS5A Inhibitors.

Non-structural 5A (NS5A) protein plays a crucial role in the replication of hepatitis C virus (HCV) and during the past decade has attracted increasing attention as a promising biological target for the treatment of viral infections and related disorders. Small-molecule NS5A inhibitors have shown significant antiviral activity in vitro and in vivo. Several lead molecules are reasonably regarded as novel highly potent drug candidates with favorable ADME features and tolerable side effects.

In Silico Approaches to the Design of NS5A Inhibitors.

In recent years, nonstructural protein 5A (NS5A) has rapidly emerged as a promising therapeutic target for Hepatitis C (HCV) virus therapy. It is involved in both viral RNA replication and virus assembly and NS5A plays a critical role in the regulation of HCV life cycle. NS5A replication complex inhibitors (NS5A RCIs) have demonstrated strong antiviral activity in vitro and in vivo.

Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists.

A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay.

Non-dopamine receptor ligands for the treatment of Parkinson's disease. Insight into the related chemical/property space.

Extensive biochemical and clinical studies have increasingly recognized Parkinson's disease as a highly complex and multi-faceted neurological disorder having branched non-motor symptoms including sleep disorders, pain, constipation, psychosis, depression, and fatigue. A wide range of biological targets in the brain deeply implicated in this pathology resulted in a plethora of novel small-molecule compounds with promising activity. This review thoroughly describes the chemical space of non-dopamine receptor ligands in terms of diversity, isosteric/bioisosteric morphing, and molecular descriptors.

Design, synthesis and biological evaluation of novel potent MDM2/p53 small-molecule inhibitors.

Regioselective synthesis, biological evaluation and 3D-molecular modeling for a series of novel diastereomeric 2-thioxo-5H-dispiro[imidazolidine-4,3-pyrrolidine-2,3-indole]-2,5(1H)-diones are described. The studied compounds have been tentatively identified as potent small molecule MDM2/p53 PPI inhibitors and can therefore be reasonably regarded as promising anticancer therapeutics.

Discovery of novel highly potent hepatitis C virus NS5A inhibitor (AV4025).

A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.

Computational approaches to the design of novel 5-HT6 R ligands.

5-Hydroxytryptamine (5-HT, serotonin) subtype 6 receptor (5-HT6 receptor, 5-HT6 R) belongs to a 5-HT subclass of a relatively wide G protein-coupled receptor (GPCR) family. Accumulated biological data indicate that 5-HT6 R antagonists and agonists have a great potential for the treatment of neuropathological disorders, such as Parkinson's disease, Alzheimer's disease, and schizophrenia. A number of painstaking efforts have been made toward the design of novel 5-HT6 R ligands; however, there are still no drugs that successfully passed all the clinical trials and entered the market, except for several multimodal ligands.

Novel oral anti-influenza drug candidate AV5080.

Objectives: Development of a novel drug candidate with improved potency against influenza virus neuraminidase compared with currently available therapeutics, and high activity against oseltamivir-resistant viruses.

Methods: A number of synthetic compounds were evaluated for antiviral properties in vitro and in vivo. Three-dimensional molecular docking, assisted by a pharmacophore model, was applied to classify compounds within the series by their inhibitory potency.

Novel oral anti-influenza prodrug candidate AV5075S.

Objectives: Development of a novel drug candidate with improved activity against influenza virus neuraminidase (NA) compared with currently available therapeutics.

Methods: Synthesized compounds were evaluated in vitro and in vivo. Three-dimensional molecular docking was successfully applied to classify compounds within the series by inhibitory potency.