A combination of structure-based virtual screening and experimental strategies to identify the potency of caffeic acid ester derivatives as SARS-CoV-2 3CL inhibitor from an in-house database.

Drug development requires significant time and resources, and computer-aided drug discovery techniques that integrate chemical and biological spaces offer valuable tools for the process. This study focused on the field of COVID-19 therapeutics and aimed to identify new active non-covalent inhibitors for 3CL, a key protein target. By combining in silico and in vitro approaches, an in-house database was utilized to identify potential inhibitors.

Investigating experimental vs. Predicted pK values for PET radiotracer.

The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood-brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pK values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pK values are often missing and published experimental pK values are limited especially for radiopharmaceuticals.

Insights and Challenges in Correcting Force Field Based Solvation Free Energies Using a Neural Network Potential.

We present a comprehensive study investigating the potential gain in accuracy for calculating absolute solvation free energies (ASFE) using a neural network potential to describe the intramolecular energy of the solute. We calculated the ASFE for most compounds from the FreeSolv database using the Open Force Field (OpenFF) and compared them to earlier results obtained with the CHARMM General Force Field (CGenFF). By applying a nonequilibrium (NEQ) switching approach between the molecular mechanics (MM) description (either OpenFF or CGenFF) and the neural net potential (NNP)/MM level of theory (using ANI-2x as the NNP potential), we attempted to improve the accuracy of the calculated ASFEs.

Reweighting from Molecular Mechanics Force Fields to the ANI-2x Neural Network Potential.

To achieve chemical accuracy in free energy calculations, it is necessary to accurately describe the system's potential energy surface and efficiently sample configurations from its Boltzmann distribution. While neural network potentials (NNPs) have shown significantly higher accuracy than classical molecular mechanics (MM) force fields, they have a limited range of applicability and are considerably slower than MM potentials, often by orders of magnitude. To address this challenge, Rufa et al.

Process Development and Scale-Up of a Novel Atypical DAT Inhibitor ()-CE-123.

Large-scale syntheses of small molecules and kilo laboratories are crucial steps in drug development, especially in advanced stages. ()-5-((Benzhydrylsulfinyl)methyl)thiazole, ()-CE-123, a potent, selective, and novel atypical DAT inhibitor, has undergone iterative testing as part of the preclinical evaluation step. This required the process transfer, scale-up, and synthesis of a 1 kg preclinical batch.

Active Learning Approach for Guiding Site-of-Metabolism Measurement and Annotation.

The ability to determine and predict metabolically labile atom positions in a molecule (also called "sites of metabolism" or "SoMs") is of high interest to the design and optimization of bioactive compounds, such as drugs, agrochemicals, and cosmetics. In recent years, several in silico models for SoM prediction have become available, many of which include a machine-learning component. The bottleneck in advancing these approaches is the coverage of distinct atom environments and rare and complex biotransformation events with high-quality experimental data.

Design, synthesis, and lead optimization of piperazinyl-pyrimidine analogues as potent small molecules targeting the viral capping machinery of Chikungunya virus.

The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimization was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimized - improving the overall yield in remarkably shorter synthesis and work-up time. Hundred analogues were designed, synthesized, and investigated for their antiviral activity, physiochemistry, and toxicological profile.

Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution.

-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of -CE-123 and -modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated.

Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach.

Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric muscarinic acetylcholine receptor ligands. Chemical reduction and bioscaffold hop lead to the development of sixteen promising compounds featuring either a benzimidazole or carbamate moiety, all exhibiting comparable pharmacophoric characteristics. The synthesized compounds were characterized by NMR, HR-MS, and RP-HPLC techniques.

Base-mediated homologative rearrangement of nitrogen-oxygen bonds of -methyl--oxyamides.

Due to the well known reactivity of C(O)-N functionalities towards canonical C1-homologating agents ( carbenoids, diazomethane, ylides), resulting in the extrusion of the -centered fragment to carbonyl compounds, formal C1-insertions within N-O bonds still remain obscure. Herein, we document the homologative transformation of -methyl--oxyamides - with high tolerance for diverse -substituents - into -acyl-,-acetals. Under controlled basic conditions, the -methyl group of the same starting materials acts as a competent precursor of the methylene synthon required for the homologation.

High-Quality Conformer Generation with CONFORGE: Algorithm and Performance Assessment.

Knowledge of the putative bound-state conformation of a molecule is an essential prerequisite for the successful application of many computer-aided drug design methods that aim to assess or predict its capability to bind to a particular target receptor. An established approach to predict bioactive conformers in the absence of receptor structure information is to sample the low-energy conformational space of the investigated molecules and derive representative conformer ensembles that can be expected to comprise members closely resembling possible bound-state ligand conformations. The high relevance of such conformer generation functionality led to the development of a wide panel of dedicated commercial and open-source software tools throughout the last decades.

Identification of Promising Sulfonamide Chalcones as Inhibitors of SARS-CoV-2 3CL through Structure-Based Virtual Screening and Experimental Approaches.

3CL is a viable target for developing antiviral therapies against the coronavirus. With the urgent need to find new possible inhibitors, a structure-based virtual screening approach was developed. This study recognized 75 pharmacologically bioactive compounds from our in-house library of 1052 natural product-based compounds that satisfied drug-likeness criteria and exhibited good bioavailability and membrane permeability.

Back in Person: Frontiers in Medicinal Chemistry 2023.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in the German speaking area and took place from April 3 to 5 2023 in Vienna (Austria). Fortunately, after being cancelled in 2020 and two years (2021-2022) of entirely virtual meetings, due to the COVID-19 pandemic, the FiMC could be held in a face-to-face format again. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh), the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (DPhG), together with the Division of Medicinal Chemistry of the Austrian Chemical Society (GÖCH), the Austrian Pharmaceutical Society (ÖPhG), and a local organization committee from the University of Vienna headed by Thierry Langer, the meeting brought together 260 participants from 21 countries.

Low-Affinity/High-Selectivity Dopamine Transport Inhibition Sufficient to Rescue Cognitive Functions in the Aging Rat.

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory.

Synthesis, analysis of mol-ecular and crystal structures, estimation of inter-molecular inter-actions and biological properties of 1-benzyl-6-fluoro-3-[5-(4-methylcyclohexyl)-1,2,4-oxadiazol-3-yl]-7-(piperidin-1-yl)quinolin-4-one.

The title compound, CHNOF, can be obtained a two-step synthetic scheme involving 1-benzyl-6-fluoro-4-oxo-7-(piperidin-1-yl)-1,4-di-hydro-quino-line-3-carbo-nitrile as a starting compound that undergoes substitution with hydroxyl-amine and subsequent cyclization with 4-methyl-cyclo-hexane-1-carb-oxy-lic acid. It crystallizes from 2-propanol in the triclinic space group with a mol-ecule of the title compound and one of 2-propanol in the asymmetric unit. After the mol-ecular structure was clarified using NMR and LC/MS, the mol-ecular and crystalline arrangements were defined with SC-XRD.

A new set of KNIME nodes implementing the QPhAR algorithm.

Dissemination of novel research methods, especially in the form of chemoinformatics software, depends heavily on their ease of applicability for non-expert users with only a little or no programming skills and knowledge in computer science. Visual programming has become widely popular over the last few years, also enabling researchers without in-depth programming skills to develop tailored data processing pipelines using elements from a repository of predefined standard procedures. In this work, we present the development of a set of nodes for the KNIME platform implementing the QPhAR algorithm.

: A Versatile Workflow for the Generation of Receptor-based Pharmacophore Models for Virtual Screening.

Pharmacophore models are widely used as efficient virtual screening (VS) filters for the target-directed enrichment of large compound libraries. However, the generation of pharmacophore models that have the power to discriminate between active and inactive molecules traditionally requires structural information about ligand-target complexes or at the very least knowledge of one active ligand. The fact that the discovery of the first known active ligand of a newly investigated target represents a major hurdle at the beginning of every drug discovery project underscores the need for methods that are able to derive high-quality pharmacophore models even without the prior knowledge of any active ligand structures.

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines.

The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer.

Novel alpha6 preferring GABA-A receptor ligands based on loreclezole.

The family of GABA-A receptors contains nineteen mammalian subunits from which pentameric, GABA gated anion channels are assembled. The subunit encoded by the GABRA6 gene is highly expressed in the cerebellum and the receptors to which it contributes have recently been demonstrated to be a promising candidate as a novel drug target. Here we examined a series of loreclezole derivatives for potentially selective action at α6β3γ2 receptors with the help of computational methods and functional testing with the two-electrode voltage clamp technique.

Pharmacophore-Based Virtual Screening and Experimental Validation of Pyrazolone-Derived Inhibitors toward Janus Kinases.

Janus kinases (JAKs) are nonreceptor protein tyrosine kinases that play a role in a broad range of cell signaling. JAK2 and JAK3 have been involved in the pathogenesis of common lymphoid-derived diseases and leukemia cancer. Thus, inhibition of both JAK2 and JAK3 can be a potent strategy to reduce the risk of these diseases.

Applications of the Novel Quantitative Pharmacophore Activity Relationship Method QPhAR in Virtual Screening and Lead-Optimisation.

Pharmacophores are an established concept for the modelling of ligand-receptor interactions based on the abstract representations of stereoelectronic molecular features. They became widely popular as filters for the fast virtual screening of large compound libraries. A lot of effort has been put into the development of sophisticated algorithms and strategies to increase the computational efficiency of the screening process.

In Silico and In Vitro Approach to Assess Direct Allosteric AMPK Activators from Nature.

The 5'-adenosine monophosphate-activated protein kinase (AMPK) is an important metabolic regulator. Its allosteric drug and metabolite binding (ADaM) site was identified as an attractive target for direct AMPK activation and holds promise as a novel mechanism for the treatment of metabolic diseases. With the exception of lusianthridin and salicylic acid, no natural product (NP) is reported so far to directly target the ADaM site.

A Novel and Selective Dopamine Transporter Inhibitor, -MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.