Small Molecules Accelerate Skin Wound Healing: Shikonin Efficacy and Mechanism of Action in Mice / Las Moléculas Pequeñas Aceleran la Curación de Heridas en la Piel: Eficacia de Shikonin y Mecanismo de Acción en Ratones

SUMMARY: The objective of this study was to investigate the therapeutic wound healing potential and molecular mechanisms of shikonin as small molecules in vitro. A mouse burn model was used to explore the potential therapeutic effect of shikonin; we traced proliferating cells in vivo to locate the active area of skin cell proliferation. Through the results of conventional pathological staining, we found that shikonin has a good effect on the treatment of burned skin and promoted the normal distribution of skin keratin at the damaged site. At the same time, shikonin also promoted the proliferation of skin cells at the damaged site; importantly, we found a significant increase in the number of fibroblasts at the damaged site treated with shikonin. Most importantly, shikonin promotes fibroblasts to repair skin wounds by regulating the PI3K/AKT signaling pathway. This study shows that shikonin can effectively promote the proliferation of skin cell, and local injection of fibroblasts in burned skin can play a certain therapeutic role.

El objetivo de este trabajo fue investigar el potencial terapéutico de cicatrización de heridas y los mecanismos moleculares de la shikonina como moléculas pequeñas in vitro. Se utilizó un modelo de quemaduras en ratones para explorar el posible efecto terapéutico de la shikonina; Rastreamos las células en proliferación in vivo para localizar el área activa de proliferación de células de la piel. A través de los resultados de la tinción para patología convencional, encontramos que la shikonina tiene un buen efecto en el tratamiento de la piel quemada y promueve la distribución normal de la queratina de la piel en el sitio dañado. Al mismo tiempo, la shikonina también promovió la proliferación de células de la piel en el sitio dañado. Es importante destacar que encontramos un aumento significativo en la cantidad de fibroblastos en el sitio dañado tratado con shikonina. Lo más importante es que la shikonina promueve la función reparadora de fibroblastos en las heridas de la piel regulando la vía de señalización PI3K/ AKT. Este estudio muestra que la shikonina puede promover eficazmente la proliferación de células de la piel y que la inyección local de fibroblastos en la piel quemada puede desempeñar un cierto papel terapéutico.

Drug repositioning in the COVID-19 pandemic: fundamentals, synthetic routes, and overview of clinical studies.

INTRODUCTION: Drug repositioning is a strategy to identify a new therapeutic indication for molecules that have been approved for other conditions, aiming to speed up the traditional drug development process and reduce its costs. The high prevalence and incidence of coronavirus disease 2019 (COVID-19) underline the importance of searching for a safe and effective treatment for the disease, and drug repositioning is the most rational strategy to achieve this goal in a short period of time. Another advantage of repositioning is the fact that these compounds already have established synthetic routes, which facilitates their production at the industrial level. However, the hope for treatment cannot allow the indiscriminate use of medicines without a scientific basis. RESULTS: The main small molecules in clinical trials being studied to be potentially repositioned to treat COVID-19 are chloroquine, hydroxychloroquine, ivermectin, favipiravir, colchicine, remdesivir, dexamethasone, nitazoxanide, azithromycin, camostat, methylprednisolone, and baricitinib. In the context of clinical tests, in general, they were carried out under the supervision of large consortiums with a methodology based on and recognized in the scientific community, factors that ensure the reliability of the data collected. From the synthetic perspective, compounds with less structural complexity have more simplified synthetic routes. Stereochemical complexity still represents the major challenge in the preparation of dexamethasone, ivermectin, and azithromycin, for instance. CONCLUSION: Remdesivir and baricitinib were approved for the treatment of hospitalized patients with severe COVID-19. Dexamethasone and methylprednisolone should be used with caution. Hydroxychloroquine, chloroquine, ivermectin, and azithromycin are ineffective for the treatment of the disease, and the other compounds presented uncertain results. Preclinical and clinical studies should not be analyzed alone, and their methodology's accuracy should also be considered. Regulatory agencies are responsible for analyzing the efficacy and safety of a treatment and must be respected as the competent authorities for this decision, avoiding the indiscriminate use of medicines.

1H NMR Profiling of the Venom from Hylesia continua: Implications of Small Molecules for Lepidopterism.

Lepidopterism caused by caterpillar contact is considered a public health problem around the world. The local and systemic responses of this pathology include short- and long-term inflammatory events. Although the proteolytic activity of the venoms from caterpillars is strongly associated with an inflammatory response in humans and murine models, fast and acute symptoms such as a burning sensation, itching, and pain should be related to the presence of low-weight hydrophilic molecules which easily influence cell metabolism. This investigation reports on the 1H-Nuclear Magnetic Resonance (NMR) profiling of the venom from the larva of Hylesia continua, a caterpillar linked to frequent cases of lepidopterism in the northern highlands of Puebla, Mexico. According to one-dimensional (1D) and two-dimensional (2D) NMR data, the venom of H. continua contained 19 compounds with proven pain-inducing activity (i.e., acetic acid, lactic acid, formic acid, succinic acid, 2-hydroxyglutaric acid, ethanol, and glutamate), inflammatory activity (i.e., cadaverine, putrescine, and acetoin), as well as natural immunosuppressive activity (i.e., O-phosphocholine and urocanic acid). The levels of the 19 compounds were calculated using quantitative-NMR (qNMR) and extensively discussed on the basis of their toxic properties which partially explain typical symptoms of lepidopterism caused by the larvae of H. continua. To the best of our knowledge, this is the first investigation reporting a complex mixture of small molecules with inflammatory properties dissolved in the venom of a lepidopteran larva.

The functional role of p38 MAPK pathway in malignant brain tumors.

Gliomas are extremely debilitating malignant brain tumors with very limited response to therapies. The initiation and progression of gliomas can be attributed to several molecular abnormalities, such as mutations in important regulatory networks. In this regard, the mitogen-activated protein kinases (MAPKs) arise as key signaling pathways involved in cell proliferation, survival, and differentiation. MAPK pathway has been altered in most glial tumors. In glioma cells, the activation of p38 MAPK contributes to tumor invasion and metastasis and is positively correlated with tumor grade, being considered a potential oncogenic factor contributing to brain tumorigenesis and chemotherapy resistance. Hence, a better understanding of glioma pathogenesis is essential to the advancement of therapies that provide extended life expectancy for glioma patients. This review aims to explore the role of the p38 MAPK pathway in the genesis and progression of malignant brain tumors.

Inibidores de JAK no tratamento da dermatite atópica / JAK inhibitors in the treatment of atopic dermatitis

A dermatite atópica é a doença inflamatória cutânea mais prevalente mundialmente. A via JAK/STAT tem papel importante no mecanismo da doença e as pequenas moléculas inibidores de JAK são fármacos com grande potencial de uso na dermatite atópica. Foi realizada uma revisão sistemática da literatura na base de dados PubMed, utilizando os termos "atopic dermatitis" e/ou "JAK inhibitors" e/ou "small molecules" entre 2017 e 2022. Foram incluídos os resultados disponíveis de estudos de fase 3, avaliando o uso de inibidores de JAK em apresentações tópicas e sistêmicas. Entre 646 estudos, foram selecionados 37 em humanos que avaliaram a eficácia e segurança dos inibidores de JAK. Os resultados do uso, quando bem indicados, mostraram-se positivos e em alguns casos superiores a outros tratamentos já preconizados para o controle da dermatite atópica, com um bom perfil de segurança.

Atopic dermatitis is the most common inflammatory skin disease worldwide. The JAK/STAT pathway plays an important role in the disease mechanism, and small-molecule JAK inhibitors are drugs with great potential for use in atopic dermatitis. We systematically reviewed PubMed using the search terms "atopic dermatitis" AND/OR "JAK inhibitors" AND/OR "small molecules" for studies published between 2017 and 2022. Results from phase III trials evaluating both topical and systemic application of JAK inhibitors were included. Of 646 studies retrieved, 37 evaluating the efficacy and safety of JAK inhibitors in humans were selected for analysis. When properly indicated, the use of JAK inhibitors yielded positive results, some of which were superior to those of recommended treatments for the control of atopic dermatitis, with a good safety profile.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/ß-Catenin Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/ß-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/ß-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/ß-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

Small molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics.

Neurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.

Challenges and Perspectives in the Discovery of Dengue Virus Entry Inhibitors.

Dengue virus (DENV) disease has become one of the major challenges in public health. Currently, there is no antiviral treatment for this infection. Since human transmission occurs via mosquitoes of the Aedes genus, most efforts have been focused on the control of this vector. However, these control strategies have not been totally successful, as reflected in the increasing number of DENV infections per year, becoming an endemic disease in more than 100 countries worldwide. Consequently, the development of a safe antiviral agent is urgently needed. In this sense, rational design approaches have been applied in the development of antiviral compounds that inhibit one or more steps in the viral replication cycle. The entry of viruses into host cells is an early and specific stage of infection. Targeting either viral components or cellular protein targets are an affordable and effective strategy for therapeutic intervention of viral infections. This review provides an extensive overview of the small organic molecules, peptides, and inorganic moieties that have been tested so far as DENV entry direct-acting antiviral agents. The latest advances based on computer-aided drug design (CADD) strategies and traditional medicinal chemistry approaches in the design and evaluation of DENV virus entry inhibitors will be discussed. Furthermore, physicochemical drug properties, such as solubility, lipophilicity, stability, and current results of pre-clinical and clinical studies will also be discussed in detail.

An Overview of Several Inhibitors for Alzheimer's Disease: Characterization and Failure.

Amyloid beta (Aß) oligomers are the most neurotoxic aggregates causing neuronal death and cognitive damage. A detailed elucidation of the aggregation pathways from oligomers to fibril formation is crucial to develop therapeutic strategies for Alzheimer's disease (AD). Although experimental techniques rely on the measure of time- and space-average properties, they face severe difficulties in the investigation of Aß peptide aggregation due to their intrinsically disorder character. Computer simulation is a tool that allows tracing the molecular motion of molecules; hence it complements Aß experiments, as it allows to explore the binding mechanism between metal ions and Aß oligomers close to the cellular membrane at the atomic resolution. In this context, integrated studies of experiments and computer simulations can assist in mapping the complete pathways of aggregation and toxicity of Aß peptides. Aß oligomers are disordered proteins, and due to a rapid exploration of their intrinsic conformational space in real-time, they are challenging therapeutic targets. Therefore, no good drug candidate could have been identified for clinical use. Our previous investigations identified two small molecules, M30 (2-Octahydroisoquinolin-2(1H)-ylethanamine) and Gabapentin, capable of Aß binding and inhibiting molecular aggregation, synaptotoxicity, intracellular calcium signaling, cellular toxicity and memory losses induced by Aß. Thus, we recommend these molecules as novel candidates to assist anti-AD drug discovery in the near future. This review discusses the most recent research investigations about the Aß dynamics in water, close contact with cell membranes, and several therapeutic strategies to remove plaque formation.

Polyamine homeostasis-based strategies for cancer: The role of combination regimens.

Spermine, spermidine and putrescine polyamines are naturally occurring ubiquitous positively charged amines and are essential metabolites for biological functions in our life. These compounds play a crucial role in many cell processes, including cellular proliferation, growth, and differentiation. Intracellular levels of polyamines depend on their biosynthesis, transport and degradation. Polyamine levels are high in cancer cells, which leads to the promotion of tumor growth, invasion and metastasis. Targeting polyamine metabolism as an anticancer strategy is considerably rational. Due to compensatory mechanisms, a single strategy does not achieve satisfactory clinical effects when using a single agent. Combination regimens are more clinically promising for cancer chemoprevention because they work synergistically with causing little or no adverse effects due to each individual agent being used at lower doses. Moreover, bioactive substances have advantages over single chemical agents because they can affect multiple targets. In this review, we discuss anticancer strategies targeting polyamine metabolism and describe how combination treatments and effective natural active ingredients are promising therapies. The existing research suggests that polyamine metabolic enzymes are important therapeutic targets and that combination therapies can be more effective than monotherapies based on polyamine depletion.

The remodel of the "central dogma": a metabolomics interaction perspective.

BACKGROUND: In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the "central dogma." Subsequently, the relationships between different steps of the "central dogma" have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the "central dogma"; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. AIM OF REVIEW: Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. KEY SCIENTIFIC CONCEPTS OF REVIEW: Metabolites are the beginning and the end of the flux of information.

Current jakinibs for the treatment of rheumatoid arthritis: a systematic review.

OBJECTIVE: One-third of patients with severe rheumatoid arthritis (RA) do not achieve remission or low disease activity, or they have side effects from cDMARD and bDMARD. They will need a new treatment option such as the small molecule JAK inhibitors. In this systematic review, we evaluate the efficacy and safety data of the current jakinibs: tofacitinib, peficitinib, decernotinib, upadacitinib, baricitinib and filgotinib in patients in whom treatment with conventional or biological disease-modifying antirheumatic drugs (cDMARD and/or bDMARD) failed. METHODS: We searched for randomized controlled trials comparing efficacy and safety of jakinibs for RA treatment using the Web of Science, Scopus, PubMed, and clinicaltrials.gov databases with the terms: "rheumatoid arthritis" OR "arthritis rheumatoid" OR "RA" AND "inhibitor" OR "jak inhibitor" AND "clinical trial" OR "treatment" OR "therapy". RESULTS: All jakinibs achieved good results in ACR 20, 50, 70 and with CRP-DAS28 for LDA and remission, upadacitinib showed better results compared to the others. In ESR-DAS28 for remission, tofacitinib achieved the best result. Regarding the safety of all jakinibs, peficitinib, baricitinib and filgotinib did not register deaths in their studies unlike tofacitinib that presented 11 deaths. Despite all benefits of jakinibs, the use in patients with severe liver and kidney disease should be avoided. CONCLUSIONS: Jakinibs in monotherapy or in combination with methotrexate can be considered a viable alternative in the treatment of moderate-to-severe RA. Even after failures with combination of cDMARDS and bDMARDS, jakinibs demonstrated efficacy.

Bioactive small molecules produced by the human gut microbiome modulate Vibrio cholerae sessile and planktonic lifestyles.

Humans live in symbiosis with a diverse community of microorganisms, which has evolved to carry out many specific tasks that benefit the host, including protection against invading pathogens. Within the chemical diversity of the gastrointestinal tract, small molecules likely constitute chemical cues for the communication between the microbiota and pathogens. Therefore, we sought to investigate if molecules produced by the human gut microbiota show biological activity against the human pathogen Vibrio cholerae. To probe the effects of the gut metabolome on V. cholerae, we investigated its response to small-molecule extracts from human feces, from a complex bacterial community cultivated in vitro, and from culture supernatants of Enterocloster citroniae, Bacteroides thetaiotaomicron, and Bacteroides vulgatus. Using RNA sequencing, we determined the impact of the human gut metabolome on V. cholerae global gene expression. Among the genes downregulated in the presence of the fecal extract, the most overrepresented functional category was cell motility, which accounted for 39% of repressed genes. Repression of V. cholerae motility by the fecal extract was confirmed phenotypically, and E. citroniae extracts reproduced this phenotype. A complex in vitro microbial community led to increased motility, as did extracts from B. vulgatus, a species present in this community. Accordingly, mucin penetration was also repressed by fecal and E. citroniae extracts, suggesting that the phenotypes observed may have implications for host colonization. Together with previous studies, this work shows that small molecules from the gut metabolome may have a widespread, significant impact on microbe-microbe interactions established in the gut environment.

Small Molecule Analysis of Extracellular Vesicles Produced by Cryptococcus gattii: Identification of a Tripeptide Controlling Cryptococcal Infection in an Invertebrate Host Model.

The small molecule (molecular mass <900 Daltons) composition of extracellular vesicles (EVs) produced by the pathogenic fungus Cryptococcus gattii is unknown, which limits the understanding of the functions of cryptococcal EVs. In this study, we analyzed the composition of small molecules in samples obtained from solid cultures of C. gattii by a combination of chromatographic and spectrometric approaches, and untargeted metabolomics. This analysis revealed previously unknown components of EVs, including small peptides with known biological functions in other models. The peptides found in C. gattii EVs had their chemical structure validated by chemical approaches and comparison with authentic standards, and their functions tested in a Galleria mellonella model of cryptococcal infection. One of the vesicular peptides (isoleucine-proline-isoleucine, Ile-Pro-Ile) improved the survival of G. mellonella lethally infected with C. gattii or C. neoformans. These results indicate that small molecules exported in EVs are biologically active in Cryptococcus. Our study is the first to characterize a fungal EV molecule inducing protection, pointing to an immunological potential of extracellular peptides produced by C. gattii.

Inkjet printing of small molecules, biologics, and nanoparticles.

During the last decades, inkjet printing has emerged as a novel technology and attracted the attention of the pharmaceutical industry, as a potential method for manufacturing personalized and customizable dosage forms to deliver drugs. Commonly, the desired drug is dissolved or dispersed within the ink and then dispensed in various dosage forms. Using this approach, several studies have been conducted to load hydrophilic or poorly water-soluble small molecules onto the surface of different solid substrates, including films, tablets, microneedles, and smart data-enriched edible pharmaceuticals, using two-dimensional and three-dimensional inkjet printing methods, with high dose accuracy and reproducibility. Furthermore, biological drugs, such as peptides, proteins, growth factors, and plasmids, have also been evaluated with positive results, eliciting the expected biological response; nonetheless, minor changes in the structure of these compounds with significant impaired activity cannot be dismissed. Another strategy using inkjet printing is to disperse drug-loaded nanoscale particles in the ink liquid, such as nanosuspension, nanocomplexes, or nanoparticles, which have been explored with promising results. Although these favorable outcomes, the proper selection of ink constituents and the inkjet printer, the correlation of printing cycles and effectively printed doses, the stability studies of drugs within the ink and the optimal analysis of samples before and after the printing process are the main challenges for inkjet printing, and therefore, this review analyzes these aspects to assess the body of current literature and help to guide future investigations on this field.

In silico approach of antiviral compounds potentials for SARS-CoV-2 and SARS-CoV and drug-like property predictions / Enfoque in silico de potenciales compuestos antivirales para SARS-CoV-2 Y SARS-CoV y predicción de propiedades drug-like

SUMMARY Introduction: SARS-CoV-2 (Coronavirus 2 of the severe acute respiratory syndrome; previously 2019-nCoV) and SARS-CoV (coronavirus of the severe acute respiratory syndrome) are closely related viruses, which have no treatment so far. Therefore, the search for new molecules is essential. Objectives: The objective of this study is to use in silico approach to propose antiviral compounds potential for SARS-CoV-2 and SARS-CoV and drug-like properties predictions. Materials and methods: Molecular docking were performed using AutoDock Vina with the molecules that had previously demonstrated drug-like properties. Subsequently, amino acids and the type of interaction involved in the protein-ligand complex were identified. Results: It was possible to identify six potential candidates available in the PubChem database capable of interacting with the 6U7 and 2GTB proteases, which bind to the same active site that lopinavir and remdesivir. Conclusion: Small molecules with drug-like properties could be used as antivirals, after experimental evaluations.

RESUMEN Introducción: Los coronavirus SARS-CoV-2 (coronavirus del síndrome respiratorio agudo grave de tipo 2; previamente identificado como 2019-nCoV) y SARS-CoV (coronavirus del síndrome respiratorio agudo grave) son virus estrechamente relacionados, que no tienen tratamiento hasta el momento. Por lo tanto, la búsqueda de nuevas moléculas es esencial. Objetivos: El objetivo de este estudio es utilizar un enfoque in silico para proponer potenciales compuestos antivirales para el SARS-CoV-2 y el SARS-CoV y predicciones de propiedades "drug-like". Materiales y métodos: El acoplamiento molecular se realizó utilizando "AutoDock Vina" con las moléculas que previamente habían demostrado propiedades similares a los fármacos. Posteriormente, se identificaron los aminoácidos y el tipo de interacción involucrada en el complejo proteína-ligando. Resultados: fue posible identificar seis candidatos potenciales disponibles en la base de datos PubChem capaces de interactuar con las proteasas 6U7 y 2GTB, que se unen al mismo sitio activo al que se unen lopinavir y remdesivir. Conclusiones: Moléculas pequeñas con propiedades similares a los fármacos podrían usarse como antivirales, después de evaluaciones experimentales.

Boronate-ester crosslinked hyaluronic acid hydrogels for dihydrocaffeic acid delivery and fibroblasts protection against UVB irradiation.

Herein, we exploit the dynamic nature and pH dependence of complexes between phenylboronic acid and diol-containing molecules to control the release of an anti-photoaging agent, dihydrocaffeic acid (DHCA), from a dynamic covalent hydrogel (HG). The HG is prepared by reversible formation of boronate ester crosslinks between hyaluronic acid (HA) modified with saccharide (GLU) residues and HA functionalized with 3-aminophenylboronic acid (APBA), part of which is involved in complexation with DHCA. The hydrogel exhibited increased dynamic moduli and a lower relaxation time at pH 7.4 in comparison to pH 6, and greater amount of DHCA was incorporated at pH 7.4. Moreover, this hydrogel prolonged DHCA release at pH 7.4 through drug reversible complexation/decomplexation, while the rate of release was fastest in acidic (skin) conditions. Very interestingly, the incorporation of DHCA into the network enhances its protection against UVB-induced L929 fibroblast death. Therefore, this smart hydrogel can contribute to photoaging prevention.

Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy.

Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. In this work, we automated the design of a library of lactams by applying a Diversity-Oriented Synthesis strategy called Build/Couple/Pair. We evaluated the novelty and diversity of these compounds by comparing them with lactam moieties contained in approved drugs, natural products, and bioactive compounds from ChEMBL. Finally, depending on their scaffold we classified them into ß-, γ-, δ-, ε-, and isolated, fused, bridged and spirolactam groups and we assessed their drug-like and lead-like properties, thus providing the value of this novel in silico designed library for medicinal chemistry applications.