Exploring a New Generation of Pyrimidine and Pyridine Derivatives as Anti-Influenza Agents Targeting the Polymerase PA-PB1 Subunits Interaction.

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and 2 (PB1 and PB2). It is widely recognized as one of the most promising anti-flu targets because of its critical role in influenza infection and high amino acid conservation. In particular, the disruption of RdRp complex assembly through protein-protein interaction (PPI) inhibition has emerged as a valuable strategy for discovering a new therapy. Our group previously identified the 3-cyano-4,6-diphenyl-pyridine core as a privileged scaffold for developing PA-PB1 PPI inhibitors. Encouraged by these findings, we synthesized a small library of pyridine and pyrimidine derivatives decorated with a thio-N-(m-tolyl)acetamide side chain (compounds 2a-n) or several amino acid groups (compounds 3a-n) at the C2 position. Interestingly, derivative 2d, characterized by a pyrimidine core and a phenyl and 4-chloro phenyl ring at the C4 and C6 positions, respectively, showed an IC50 value of 90.1 µM in PA-PB1 ELISA, an EC50 value of 2.8 µM in PRA, and a favorable cytotoxic profile, emerging as a significant breakthrough in the pursuit of new PPI inhibitors. A molecular modeling study was also completed as part of this project, allowing us to clarify the biological profile of these compounds.

Recent Advances of Natural Pentacyclic Triterpenoids as Bioactive Delivery System for Synergetic Biological Applications.

Bioactive compounds have drawn much attention according to their various health benefits. However, poor dissolvability, low stability and limited bioavailability largely narrow their applications. Although a variety of nontoxic ingredients have been rapidly developed as vehicles to deliver bioactive compounds in the last few years, most of them are non-bioactive. Pentacyclic triterpenoids, owing to their unique self-assembly and co-assembly behaviors and different physiological functions, can construct bioactive carriers due to their higher biodegradability, biocompatibility and lower toxicity. In this paper, the basic classification, biological activities and physicochemical properties of pentacyclic triterpenoids were summarized. Additionally, applications of self-assembled and co-assembled pentacyclic triterpenoids as bioactive delivery systems to load bioactive components and future research directions were discussed. This study emphasizes the potential of pentacyclic triterpenoids as bioactive delivery systems, offering a new perspective for constructing self- or co-assemblies for further synergetic biological applications.

Biologics and small molecules treatment for moderate-to-severe atopic dermatitis patients with comorbid conditions and special populations: an Italian perspective.

This comprehensive review offers a detailed look at atopic dermatitis (AD) treatment in Italy, focusing primarily on the use of biologics and small molecules. In response to advancing knowledge of AD's causes and treatments, there's a global need for updated guidelines to provide physicians with a more comprehensive clinical perspective, facilitating personalized treatment strategies. Dupilumab, a groundbreaking biologic, gained approval as a significant milestone. Clinical trials demonstrated its ability to significantly reduce AD severity scores, with an impressive 37% of patients achieving clear or nearly clear skin within just 16 weeks of treatment. Real-world studies further support its efficacy across various age groups, including the elderly, with a safety profile akin to that of younger adults. Tralokinumab, a more recent approval, shows promise in clinical trials, particularly among younger populations. However, its real-world application, especially in older individuals, lacks comprehensive data. Janus Kinases inhibitors like Upadacitinib, Baricitinib, and Abrocitinib hold substantial potential for AD treatment. Nevertheless, data remains limited for patients over 75, with older adults perceived to carry a higher risk profile. Integrated safety analyses revealed individuals aged 60 and above experiencing major adverse cardiovascular events and malignancies, underscoring the need for cautious consideration. While these therapies offer promise, especially among younger patients, further research is essential to determine their safety and efficacy in various populations, including pediatric, geriatric, and those with comorbidities. Biologics and small molecules are improving AD treatment, as shown in this review.

Argonaute protein assisted drug discovery for miRNA-181c-5p and target gene ATM translation repression: a computational approach.

The miRNA binds to AGO's seed region, prompting the exploration of small molecules that can offset miRNA repression of target mRNA. This miRNA-181c-5p was found to be upregulated in the chronic traumatic encephalopathy, a prevalent neurodegenerative disease in contact sports and military personals. The research aimed to identify compounds that disrupt the AGO-assisted loop formation between miRNA-181c-5p and ATM, consequently repressing the translation of ATM. Target genes from commonly three databases (DIANA-microT-CDS, miRDB, RNA22 and TargetScan) were subjected to functional annotation and clustering analysis using DAVID bioinformatics tool. Haddock server were employed to make miRNA-181c-5p:ATM-AGO complex. A total of 2594 small molecules were screened using Glide XP based on their highest binding affinity towards the complex, through a three-phase docking approach. The top 5 compounds (DB00674-Galantamine, DB00371-Meprobamate, DB00694-Daunorubicin, DB00837-Progabide, and DB00851-Dacarbazine) were further analyzed for stability in the miRNA-181c-5p:ATM-AGO-ligand complex interaction using GROMACS (version 2023.2). Hence, these findings suggest that these molecules hold potential for facilitating AGO-assisted repression of ATM gene translation.

Breaking barriers: Innovative approaches for skin delivery of RNA therapeutics.

RNA therapeutics represent a rapidly expanding platform with game-changing prospects in personalized medicine. The disruptive potential of this technology will overhaul the standard of care with reference to both primary and specialty care. To date, RNA therapeutics have mostly been delivered parenterally via injection, but topical administration followed by intradermal or transdermal delivery represents an attractive method that is convenient to patients and minimally invasive. The skin barrier, particularly the lipid-rich stratum corneum, presents a significant hurdle to the uptake of large, charged oligonucleotide drugs. Therapeutic oligonucleotides need to be engineered for stability and specificity and formulated with state-of-the-art delivery strategies for efficient uptake. This review will cover various passive and active strategies deployed to enhance permeation through the stratum corneum and achieve effective delivery of RNA therapeutics to treat both local skin disorders and systemic diseases. Some strategies to achieve selectivity between local and systemic administration will also be discussed.

Detouring Self-Assembled 3-Methoxy-pyrrole-Based Nanoparticles into Mitochondria to Induce Apoptosis in Lung Cancer Cells.

Lung cancer remains a lethal disease globally. Recently, the development and progression of lung cancer were strongly linked with mitochondrial dysfunction. Hence, targeting mitochondria in lung cancer can be an interesting alternative strategy for therapeutic applications. To address this, we have designed and synthesized a 3-methoxy-pyrrole-enamine-triphenylphosphonium cation-based library through a concise chemical strategy. Upon screening this library in cervical (HeLa), colon (HCT-116), breast (MCF7), and lung (A549) cancer cells, we identified a small molecule that self-assembled into nanoscale spherical particles with a positive surface charge. This nanoparticle was confined to the mitochondria to induce mitochondrial damage and produced reactive superoxide in A549 cells. This small molecule self-assembled nanoparticle-mediated mitochondrial damage triggered apoptosis leading to the remarkable killing of A549 cells. These 3-methoxy-pyrrole-enamine-triphenylphosphonium nanoparticles can be used as a tool to understand the chemical biology of mitochondria in lung cancer for chemotherapeutic applications.

Inhibitors of the transactivation domain of androgen receptor as a therapy for prostate cancer.

The androgen receptor (AR) is a modular transcription factor which functions as a master regulator of gene expression. AR protein is composed of three functional domains; the ligand-binding domain (LBD); DNA-binding domain (DBD); and the intrinsically disordered N-terminal transactivation domain (TAD). AR is transactivated upon binding to the male sex hormone testosterone and other androgens. While the AR may tolerate loss of its LBD, the TAD contains activation function-1 (AF-1) that is essential for all AR transcriptional activity. AR is frequently over-expressed in most prostate cancer. Currently, androgen deprivation therapy (ADT) in the form of surgical or chemical castration remains the standard of care for patients with high risk localized disease, advanced and metastatic disease, and those patients that experience biochemical relapse following definitive primary treatment. Patients with recurrent disease that receive ADT will ultimately progress to lethal metastatic castration-resistant prostate cancer. In addition to ADT not providing a cure, it is associated with numerous adverse effects including cardiovascular disease, osteoporosis and sexual dysfunction. Recently there has been a renewed interest in investigating the possibility of using antiandrogens which competitively bind the AR-LBD without ADT for patients with hormone sensitive, non-metastatic prostate cancer. Here we describe a class of compounds termed AR transactivation domain inhibitors (ARTADI) and their mechanism of action. These compounds bind to the AR-TAD to inhibit AR transcriptional activity in the absence and presence of androgens. Thus these inhibitors may have utility in preventing prostate cancer growth in the non-castrate setting.

A Review on Small Molecule Based Fluorescence Chemosensors for Bioimaging Applications.

This review provides a thorough examination of small molecule-based fluorescence chemosensors tailored for bioimaging applications, showcasing their unique ability to visualize biological processes with exceptional sensitivity and selectivity. It explores recent advancements, methodologies, and applications in this domain, focusing on various designs rooted in anthracene, benzothiazole, naphthalene, quinoline, and Schiff base. Structural modifications and molecular engineering strategies are emphasized for enhancing sensor performance, including heightened sensitivity, selectivity, and biocompatibility. Additionally, the review offers valuable insights into the ongoing development and utilization of these chemosensors, addressing current challenges and charting future directions in this rapidly evolving field.

Highly sensitive antibiotic sensing based on optical weak value amplification: A case study of chloramphenicol.

The public health concern of antibiotic residues in animal-origin food has been a long-standing issue. In this work, we present a novel method for antibiotic detection, leveraging optical weak value amplification and harnessing an indirect competitive inhibition assay, which significantly boosts the system's sensitivity in identifying small molecule antibiotics. We chose chloramphenicol as a model compound and mixed it with chloramphenicol-bovine serum albumin conjugates to bind to the chloramphenicol antibody competitively. We achieved a broad linear detection range of up to 3.24 ng/mL and a high concentration resolution of 33.20 pg/mL. To further validate the universality of our proposed detection methodology, we successfully applied it to testing gibberellin and tetracycline. Moreover, we conducted regeneration experiments and real-sample correlation studies. This study introduces a novel strategy for the label-free optical sensing of small molecule antibiotics, greatly expanding the range of applications for sensors utilizing optical weak value amplification.

DrugDomain: The evolutionary context of drugs and small molecules bound to domains.

Interactions between proteins and small organic compounds play a crucial role in regulating protein functions. These interactions can modulate various aspects of protein behavior, including enzymatic activity, signaling cascades, and structural stability. By binding to specific sites on proteins, small organic compounds can induce conformational changes, alter protein-protein interactions, or directly affect catalytic activity. Therefore, many drugs available on the market today are small molecules (72% of all approved drugs in the last 5 years). Proteins are composed of one or more domains: evolutionary units that convey function or fitness either singly or in concert with others. Understanding which domain(s) of the target protein binds to a drug can lead to additional opportunities for discovering novel targets. The evolutionary classification of protein domains (ECOD) classifies domains into an evolutionary hierarchy that focuses on distant homology. Previously, no structure-based protein domain classification existed that included information about both the interaction between small molecules or drugs and the structural domains of a target protein. This data is especially important for multidomain proteins and large complexes. Here, we present the DrugDomain database that reports the interaction between ECOD of human target proteins and DrugBank molecules and drugs. The pilot version of DrugDomain describes the interaction of 5160 DrugBank molecules associated with 2573 human proteins. It describes domains for all experimentally determined structures of these proteins and incorporates AlphaFold models when such structures are unavailable. The DrugDomain database is available online: http://prodata.swmed.edu/DrugDomain/.

A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Endothelial dysfunction: Pathophysiology and therapeutic targets for sepsis-induced multiple organ dysfunction syndrome.

Sepsis and septic shock are critical medical conditions characterized by a systemic inflammatory response to infection, significantly contributing to global mortality rates. The progression to multiple organ dysfunction syndrome (MODS) represents the most severe complication of sepsis and markedly increases clinical mortality. Central to the pathophysiology of sepsis, endothelial cells play a crucial role in regulating microcirculation and maintaining barrier integrity across various organs and tissues. Recent studies have underscored the pivotal role of endothelial function in the development of sepsis-induced MODS. This review aims to provide a comprehensive overview of the pathophysiology of sepsis-induced MODS, with a specific focus on endothelial dysfunction. It also compiles compelling evidence regarding potential small molecules that could attenuate sepsis and subsequent multi-organ damage by modulating endothelial function. Thus, this review serves as an essential resource for clinical practitioners involved in the diagnosing, managing, and providing intensive care for sepsis and associated multi-organ injuries, emphasizing the importance of targeting endothelial cells to enhance outcomes of the patients.

Study of Ammonia Adsorption on Magnetite Surfaces with Molecular Dynamics Simulations.

The present study proposes an atomistic molecular dynamics model system of a magnetite (Fe3O4) {111} surface. The effect of temperature on the adsorption process of ammonia (NH3) at low concentrations in the aqueous phase has been considered. The molecular dynamics simulations were carried out using the Clay force field (Clay FF) with a modification for the iron atoms in the NPT ensemble at a pressure of 90 bar. The considered system was heated in a temperature range from 293 to 473 K, and additional relaxations were performed at temperatures of interest. Within the scope of this study, the basic parameters of the magnetite surface were calculated and the distances between the ammonia molecules and the surface were determined. A general idea of the degree and rate of adsorption at specific temperatures was obtained. The calculation results were compared to the experimental data where possible and to other available simulations of adsorption processes on metal oxides.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient's quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

NMR structures of small molecules bound to a model of a CUG RNA repeat expansion.

Trinucleotide repeat expansions fold into long, stable hairpins and cause a variety of incurable RNA gain-of-function diseases such as Huntington's disease, the myotonic dystrophies, and spinocerebellar ataxias. One approach for treating these diseases is to bind small molecules to these structured RNAs. Both Huntington's disease-like 2 (HDL2) and myotonic dystrophy type 1 (DM1) are caused by a r(CUG) repeat expansion, or r(CUG)exp. The RNA folds into a hairpin structure with a periodic array of 1 × 1 nucleotide UU loops (5'CUG/3'GUC; where the underlined nucleotides indicate the Us in the internal loop) that sequester various RNA-binding proteins (RBPs) and hence the source of its gain-of-function. Here, we report nuclear magnetic resonance (NMR)-refined structures of single 5'CUG/3'GUC motifs in complex with three different small molecules, a di-guandinobenzoate (1), a derivative of 1 where the guanidino groups have been exchanged for imidazole (2), and a quinoline with improved drug-like properties (3). These structures were determined using NMR spectroscopy and simulated annealing with restrained molecular dynamics (MD). Compounds 1, 2, and 3 formed stacking and hydrogen bonding interactions with the 5'CUG/3'GUC motif. Compound 3 also formed van der Waals interactions with the internal loop. The global structure of each RNA-small molecule complexes retains an A-form conformation, while the internal loops are still dynamic but to a lesser extent compared to the unbound form. These results aid our understanding of ligand-RNA interactions and enable structure-based design of small molecules with improved binding affinity for and biological activity against r(CUG)exp. As the first ever reported structures of a r(CUG) repeat bound to ligands, these structures can enable virtual screening campaigns combined with machine learning assisted de novo design.

Artificial intelligence for small molecule anticancer drug discovery.

INTRODUCTION: The transition from conventional cytotoxic chemotherapy to targeted cancer therapy with small-molecule anticancer drugs has enhanced treatment outcomes. This approach, which now dominates cancer treatment, has its advantages. Despite the regulatory approval of several targeted molecules for clinical use, challenges such as low response rates and drug resistance still persist. Conventional drug discovery methods are costly and time-consuming, necessitating more efficient approaches. The rise of artificial intelligence (AI) and access to large-scale datasets have revolutionized the field of small-molecule cancer drug discovery. Machine learning (ML), particularly deep learning (DL) techniques, enables the rapid identification and development of novel anticancer agents by analyzing vast amounts of genomic, proteomic, and imaging data to uncover hidden patterns and relationships. AREA COVERED: In this review, the authors explore the important landmarks in the history of AI-driven drug discovery. They also highlight various applications in small-molecule cancer drug discovery, outline the challenges faced, and provide insights for future research. EXPERT OPINION: The advent of big data has allowed AI to penetrate and enable innovations in almost every stage of medicine discovery, transforming the landscape of oncology research through the development of state-of-the-art algorithms and models. Despite challenges in data quality, model interpretability, and technical limitations, advancements promise breakthroughs in personalized and precision oncology, revolutionizing future cancer management.