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Discovering new drugs to treat central nervous system (CNS) disease involves establishing high-throughput screening (HTS) formats for central phenotypes such as neuroinflammation, oxidative stress, pathological proteins, hyperexcitability, and neuroplasticity. A range of complex and patient-based models exist to discover new drugs for these phenotypes; however, certain trade-offs between clinical relevance and scalability need to be carefully considered. While most CNS drug discovery studies have employed chemogenomic-based compound libraries, new fragment-based approaches are emerging that offer distinct advantages. The design of the screening cascade for hit-to-lead studies is often key to the success of CNS phenotypic drug discovery, with experimental and artificial intelligence (AI) target identification approaches now playing an important role in this process. Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote clinical translation of drugs by reducing complex brain diseases to measurable, clinically valid phenotypes. We critique recent platforms integrating patient-derived brain cells, which most accurately recapitulate CNS disease phenotypes, with higher throughput models, including immortalized cells, to balance validity and scalability. These platforms were screened with conventional commercial chemogenomic compound libraries. We explore emerging library curation strategies to improve hit rate and quality, and screening novel fragment libraries as alternatives, for more tractable drug target deconvolution. The clinically relevant models used in these platforms could harbor important, unidentified drug targets, so we review evolving agnostic target deconvolution approaches, including chemical proteomics and artificial intelligence (AI), which aid in phenotypic screening hit mechanism elucidation, thereby facilitating rational hit-to-drug optimization. [ABSTRACT FROM AUTHOR]

Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (<−9.00 kcal/mol), surpassing that of RdRp-ribavirin (<−7.00 kcal/mol) along with promising ADMET score predictions (<4.00), of which (LYCR728-210, LYCS728-210, LYCR728-212, LYCS505-214) displayed binding properties to both DENV3 and ZIKV targets. Our research highlights the potential of non-nucleoside lycorine-based analogs with different enantiomers that may present different or even completely opposite metabolic, toxicological, and pharmacological profiles as promising candidates for inhibiting NS5-RdRp in ZIKV and DENV3, paving the way for further exploration for the development of effective antiviral agents. [ABSTRACT FROM AUTHOR]

Dengue (DENV) and Zika (ZIKV) virus continue to pose significant challenges globally due to their widespread prevalence and severe health implications. Given the absence of effective vaccines and specific therapeutics, targeting the highly conserved NS5 RNA-dependent RNA polymerase (RdRp) domain has emerged as a promising strategy. However, limited efforts have been made to develop inhibitors for this crucial target. In this study, we employed an integrated in silico approach utilizing combinatorial chemistry, docking, molecular dynamics simulations, MM/GBSA, and ADMET studies to target the allosteric N-pocket of DENV3-RdRp and ZIKV-RdRp. Using this methodology, we designed lycorine analogs with natural S-enantiomers (LYCS) and R-enantiomers (LYCR) as potential inhibitors of non-structural protein 5 (NS5) in DENV3 and ZIKV. Notably, 12 lycorine analogs displayed a robust binding free energy (

Background: Metastasis poses the greatest threat to the lives of individuals with prostate cancer. Therefore, it is imperative to identify the underlying mechanism driving metastasis. Doing so would facilitate the detection of new diagnostic biomarkers and the advancement of treatment options for patients. Methods: Metastasis‐related modules were identified through weighted gene co‐expression network analysis based on microarray GSE6919. Hub genes were confirmed by quantitative real‐time PCR across different prostate cell lines and clinic samples. Pivotal genes were determined through integration of RNA and transcription factor‐target associated interactions. To predict drugs with potential to suppress tumor metastasis, we applied molecular networks using the DrugBank database. Drug repositioning analysis and confirmation of drug screen were conducted using the compound library. Confirmation of selective cytotoxicity of cupric oxide was carried out via invasion, transwell and apoptosis assays. Results: We identified five metastasis‐related modules. Of these modules, two were identified to represent core dysfunction modules in which five hub genes were determined for each module. Five of these 10 genes correlating with prostate cancer progression. Furthermore, our analysis revealed that there are 36 drugs with the potential to be active against tumor metastasis. Finally, we identified four compounds that have not previously been reported to have any association with cancer therapy. Of these, cupric oxide was determined to have the best chemotherapeutic potential in treating prostate cancer metastasis. Conclusions: By combining bioinformatics methods with compound library screening, this study proposes a valuable approach to drug discovery. Cupric oxide showed the potential in the treatment of prostate cancer metastasis and deserves further study. [ABSTRACT FROM AUTHOR]

Definition: Efficient chemical library design for high-throughput virtual screening and drug design requires a pre-screening filter pipeline capable of labeling aggregators, pan-assay interference compounds (PAINS), and rapid elimination of swill (REOS); identifying or excluding covalent binders; flagging moieties with specific bio-evaluation data; and incorporating physicochemical and pharmacokinetic properties early in the design without compromising the diversity of chemical moieties present in the library. This adaptation of the chemical space results in greater enrichment of hit lists, identified compounds with greater potential for further optimization, and efficient use of computational time. A number of medicinal chemistry filters have been implemented in the Konstanz Information Miner (KNIME) software and analyzed their impact on testing representative libraries with chemoinformatic analysis. It was found that the analyzed filters can effectively tailor chemical libraries to a lead-like chemical space, identify protein–protein inhibitor-like compounds, prioritize oral bioavailability, identify drug-like compounds, and effectively label unwanted scaffolds or functional groups. However, one should be cautious in their application and carefully study the chemical space suitable for the target and general medicinal chemistry campaign, and review passed and labeled compounds before taking further in silico steps. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZDs), also known as Glitazones, have anti-diabetic, anti-inflammatory and anti-cancer properties. A simple, efficient and cost-effective synthesis of a thiazolidinedione compound library was developed. The synthesis is facilitated by microwave irradiation in three of the four steps followed by reduction under pressurized hydrogen gas using palladium hydroxide. All reactions, except one, were completed within an hour and provided desired products in moderate to good yields after a simple work-up. [ABSTRACT FROM AUTHOR]

Response to anticancer agents is often restricted to subsets of patients. Recognition of factors underlying this heterogeneity and identification of biomarkers associated with response to drugs would greatly improve the efficacy of drug treatment. Platforms that can comprehensively map cellular response to compounds in high-throughput provide a unique tool to identify associated biomarkers and provide hypotheses for mechanisms underlying variable response. Such screens can be performed on cell lines and short-term cultures of primary cells to take advantage of the respective models' strength, which include, e.g., the ability to silence genes or introduce somatic mutations to cell lines. Cohorts of patient samples represent the natural diversity of cancers, including rarer mutations and combinatorial patterns of mutations that are often absent from existing cell lines. We here summarize a simple and scalable method for the measurement of viability after drug exposure based on ATP measurements as a surrogate for viability, which we use to measure and understand drug response in cell lines and primary cells., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

High throughput analysis is increasingly relevant in both industry and academia, with applications reaching from enzymology and drug discovery to organic reaction optimization and diagnostics. Currently, chromatography-free mass spectrometry (MS) techniques have acquired an important role in this field due to their inherent speed, versatility, and chemical specificity. Desorption electrospray ionization (DESI) MS is one of these approaches, which allows for direct analysis of complex samples in the ambient environment, with throughputs better than 1 sample per second and no need for sample treatment. Here we assess the evolution of the high throughput DESI-MS analytical performance from the early DESI source developed by Prosolia Inc. to the recently commercialized version of Waters Corporation. The evaluation was carried out through both quantitative and qualitative analysis of biologically relevant compounds including metabolites, peptides, lipids and pharmaceuticals. Our results indicate that both platforms are successful at the direct analysis of these species even from complex matrices such as bioassay buffers. However, the newest iteration of the DESI stage, when combined with a quadrupole time-of-flight (Q-ToF) instrument, provides higher sensitivity (1-3 orders of magnitude lower limits of detection) and reproducibility (ca. 10% average reduction in coefficients of variation for quantitation using an internal standard). The cases explored in this study also showcase the broad applicability of high throughput DESI-MS for bioanalysis and quality control.

• The updated ELF library is available for screening by academics, SMEs, and charities. • The library contains 300k compounds from pharma and 200k completely novel compounds. • The library can be screened in target-focused, target-agnostic, and HCI assays. Through the European Lead Factory model, industry-standard high-throughput screening and hit validation are made available to academia, small and medium-sized enterprises, charity organizations, patient foundations, and participating pharmaceutical companies. The compound collection used for screening is built from a unique diversity of sources. It brings together compounds from companies with different therapeutic area heritages and completely new compounds from library synthesis. This generates structural diversity and combines molecules with complementary physicochemical properties. In 2019, the screening library was updated to enable another 5 years of running innovative drug discovery projects. Here, we investigate the physicochemical and diversity properties of the updated compound collection. We show that it is highly diverse, drug-like, and complementary to commercial screening libraries. [ABSTRACT FROM AUTHOR]

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C−H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal‐catalyzed C−H functionalization of a "programmed" 4‐hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity‐oriented functionalization, of which four were targeted. The C‐2 and C‐8 decorations were directed by an N‐oxide, before taking benefit of an O‐carbamoyl protection at C‐4 to perform a Fries rearrangement and install a carboxamide at C‐3. This also released the carbonyl group of 4‐quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C−H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential. [ABSTRACT FROM AUTHOR]

Plasmid conjugation is an important contributing factor to the spread of antibiotic resistance among bacteria, posing a significant global health threat. Our method introduces an innovative high-throughput screening approach to identify compounds that inhibit or reduce conjugation, addressing the need for new strategies against the spread of antimicrobial resistance. Using Escherichia coli strains as donor and recipient, we screened 3500 compounds from a library provided by ABAC Therapeutics. Each 96 -well plate was loaded with 88 different compounds and bacterial cultures. Every plate also included negative and positive controls of conjugation. After an hour, cultures from wells were spotted on agar plates and assessed visually. Compounds that showed a visible effect on conjugation were retested. Six compounds targeting conjugation were found, showing promise for further analysis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Domingo Gargallo-Viola is CEO at ABAC Therapeutics S.L. The company works on finding new pathogen-specific compounds with novel mechanisms of action. Domingo Gargallo-Viola has provided the compound library used for setting up the method described in this paper., (© 2024 The Authors.)

Despite the fact that significant advances in treatment of common cancers have been achieved over the years, orphan tumors still represent an important unmet medical need. Due to their complex multifactorial origin and limited number of cases, such pathologies often have very limited treatment options and poor prognosis. In the search for new anticancer agents, our group recently identified RC-106, a Sigma receptor modulator endowed with proteasome inhibition activity. This compound showed antiproliferative activity toward different cancer cell lines, among them glioblastoma (GB) and multiple myeloma (MM), two currently unmet medical conditions. In this work, we directed our efforts toward the exploration of chemical space around RC-106 to identify new active compounds potentially useful in cancer treatment. Thanks to a combinatorial approach, we prepared 41 derivatives of the compound and evaluated their cytotoxic potential against MM and GB. Three novel potential anticancer agents have been identified.

Click chemistry has emerged as a valuable tool for rapid compound synthesis, presenting notable advantages and convenience in the exploration of potential drug candidates. In particular, in situ click chemistry capitalizes on enzymes as reaction templates, leveraging their favorable conformation to selectively link individual building blocks and generate novel hits. This review comprehensively outlines and introduces the extensive use of click chemistry in compound library construction, and hit and lead discovery, supported by specific research examples. Additionally, it discusses the limitations and precautions associated with the application of click chemistry in drug discovery. Our intention for this review is to contribute to the development of a modular synthetic approach for the rapid identification of drug candidates. [Display omitted] • Click chemistry is a valuable strategy to accelerate drug discovery. • The application of click chemistry in compound library construction was reviewed. • The extensive use of click chemistry in hit and lead discovery was summarized. • The limitations and precautions of click chemistry were discussed. [ABSTRACT FROM AUTHOR]

This chapter intends to provide a general overview of web-based resources available for antiviral drug discovery studies. First, we explain how the structure for a potential viral protein target can be obtained and then highlight some of the main considerations in preparing for the application of receptor-based molecular docking techniques. Thereafter, we discuss the resources to search for potential drug candidates (ligands) against this target protein receptor, how to screen them, and preparing their analogue library. We make specific reference to free, online, open-source tools and resources which can be applied for antiviral drug discovery studies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

1,3‐unsubstituted 2‐(1H‐indol‐2‐yl)ethanamines were employed for the first time to react with alkynoic acids (AAs) to achieve gold‐catalyzed highly selective cascade reactions to furnish novel indole‐fused skeletons. Furthermore, with this powerful gold catalytic system, a library of indole/pyrrole/thiophene/benzene/naphthalene/pyridine‐based nitrogen‐containing heterocyclic compounds (NCHCs) with scaffold diversity and molecular complexity was constructed rapidly using various amine nucleophiles (ANs) and diverse AAs as the building blocks. This general protocol features excellent selectivity, extraordinarily broad substrate scope, readily available inputs, good to high yields, high bond‐forming efficiency, and step economy, thus providing a facile and efficient access to a variety of valuable nitrogen‐containing heterocycles. [ABSTRACT FROM AUTHOR]

Flow chemistry is one of the most prominent enabling technologies that has greatly shaped the way chemists’ approach organic synthesis. Specifically, in drug discovery, the advantages of flow techniques over batch procedures allow the rapid and efficient assembly of compound libraries to be tested for biological properties. The aim of the present review is to comment on some representative examples from the last five years of literature that highlight how flow procedures are becoming of increasing importance for the synthesis of biologically-relevant molecules.

We herein describe a flexible synthesis of a small library of 68Ga-labeled CAIX-targeted molecules via an orthogonal 2-cyanobenzothiazole (CBT)/1,2-aminothiol click reaction. Three novel CBT-functionalized chelators (1–3) were successfully synthesized and labeled with the positron emitter gallium-68. Cross-ligation between the pre-labeled bifunctional chelators (BFCs) and the 1,2-aminothiol-acetazolamide derivatives (8 and 9) yielded six new 68Ga-labeled CAIX ligands with high radiochemical yields. The click reaction conditions were optimized to improve the reaction rate for applications with short half-life radionuclides. Overall, our methodology allows for a simple and efficient radiosynthetic route to produce a variety of 68Ga-labeled imaging agents for tumor hypoxia.

Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds ( 2 – 64 ), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC 50 values ranging 0.3–4.8 μM) than the lead (IC 50 values ranging 1.3–10.1 μM) either in lag or log growth phases. SAR analysis revealed that acylation enhances cytotoxicity, suggesting the hydrophobic moiety contributes to the activity, presumably by increasing affinity and/or cell membrane permeability. Further investigation clearly indicated that compounds 3 , 11 , 12 , and 18 induce apoptosis evidenced by chromatin condensation, phosphatidylserine externalization, and caspase-3 activation effects on HeLa cells. The potent capacity to induce apoptosis with concomitant cell loss in G2/M highlights the potential of 27-benzyl analogue ( 18 ) as an apoptotic inducer drug candidate. [ABSTRACT FROM AUTHOR]

In this report we utilized zebrafish ( Danio rerio ) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10 μM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC 50 = 4.078 μM) and surprisingly a DAPK1 kinase agonist/activator (EC 50 = 39.525 μM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways. [ABSTRACT FROM AUTHOR]

We describe here a novel chemotype with substituted benzimidazole scaffold for nonsteroidal farnesoid X receptor (FXR) antagonists starting from the identification of a screening hit, BB-4 . Structure diversity in four regions A-D of BB-4 or 1 is discussed. In particular, regions A and C had an effect on an antagonism against FXR as demonstrated by the derivatives represented by 7 and 15 , respectively. Thus, compound 19 arising from the combination of regions A and C underscored an important fact on antagonism against FXR, also showing the reduced small heterodimer partner and the increased cholesterol 7α-hydroxylase expression levels. [ABSTRACT FROM AUTHOR]

A simple and efficient method for the synthesis of highly substituted spiroindoline derivatives is presented. A Fischer indolization is combined with Ugi-type reactions to explore the chemical space concerning this privileged structure. Moreover, spiropiperidine derivatives could be postmodified for the production of a small-molecule library that will be part of the Joint European Compound Library of the European Lead Factory. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cellbased assays comparable to the Zardaverine control used, suggesting potential avenues for their further development. [ABSTRACT FROM AUTHOR]

Adenosine kinase (AdK) is a key player in controlling intra- and extracellular concentrations of the signaling molecule adenosine. Extensive evidence points to an important role of AdK in several diseases, and suggests that AdK inhibition might be a promising therapeutic strategy. The development of a new AdK assay and subsequent screening of part of our focused compound library led to the identification of 12 hit compounds (hit rate of 6%) representing six new classes of non-nucleoside human AdK inhibitors. The most potent inhibitor 1 displayed a K i value of 184 nM. Compound screening with a newly developed assay was useful and efficient for discovering novel AdK inhibitors which may serve as lead structures for developing drugs for adenosine augmentation therapy. [ABSTRACT FROM AUTHOR]

Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library. [ABSTRACT FROM AUTHOR]

A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3- a ]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3- a ]quinolizines was generated and submitted to European lead factory consortium for various biological screenings. [ABSTRACT FROM AUTHOR]

Apoptosis signal-regulating kinase 1 (ASK1) plays important roles in the pathogenesis of type 1 and type 2 diabetes, autoimmune disorders, cancer and neurodegenerative diseases suggesting that small compounds inhibiting ASK1 could be used for the treatment of these pathologies. We have identified novel chemical class of ASK1 inhibitors, namely benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC 50 of 0.52 μM in vitro in kinase assay. The structure–activity relationships of 34 derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed. [ABSTRACT FROM AUTHOR]

The identification of hits and the generation of viable leads is an early and yet crucial step in drug discovery. In the West, the main players of drug discovery are pharmaceutical and biotechnology companies, while in China, academic institutions remain central in the field of drug discovery. There has been a tremendous amount of investment from the public as well as private sectors to support infrastructure buildup and expertise consolidation relative to drug discovery and development in the past two decades. A large-scale compound library has been established in China, and a series of high-impact discoveries of lead compounds have been made by integrating information obtained from different technology-based strategies. Natural products are a major source in China’s drug discovery efforts. Knowledge has been enhanced via disruptive breakthroughs such as the discovery of Boc5 as a nonpeptidic agonist of glucagon-like peptide 1 receptor (GLP-1R), one of the class B G protein–coupled receptors (GPCRs). Most of the original hit identification and lead generation were carried out by academic institutions, including universities and specialized research institutes. The Chinese pharmaceutical industry is gradually transforming itself from manufacturing low-end generics and active pharmaceutical ingredients to inventing new drugs. [ABSTRACT FROM PUBLISHER]