👤 Wink DA

Artificial intelligence (AI) is being used in oncological drug development to address the high costs, low success rates, and long timelines that characterize traditional drug development pipelines. The use of machine learning (ML) and deep learning (DL) models in computer-aided drug design is constantly growing owing to their capacity to analyze large, heterogeneous datasets, their ability to capture nonlinear biological trends, and their integration of various molecular and clinical characteristics. AI applications accelerate target discovery by predicting protein structures, ranking disease-relevant genes, and assessing target drugability. AI can be used to conduct rapid searches of multiplexed chemical libraries, predict drug-target interactions, and optimize the pharmacological and physicochemical properties of drugs in virtual screening. Advanced neural network designs also aid in de novo drug design, which involves developing new molecular structures with therapeutic properties of interest. This review outlines how AI has been used for target identification, virtual screening, de novo molecular design, and, specifically, in cancer applications. It further discusses the major issues in AI-based drug development, such as data quality, model interpretation, computational constraints, and ethical and regulatory considerations, which remain essential obstacles to broader clinical translation. Show less

Small redox active molecules such as reactive nitrogen and oxygen species and hydrogen sulfide have emerged as important biological mediators that are involved in various physiological and pathophysiological processes. Advancement in understanding of cellular mechanisms that tightly regulate both generation and reactivity of these molecules is central to improved management of various disease states including cancer and cardiovascular dysfunction. Imbalance in the production of redox active molecules can lead to damage of critical cellular components such as cell membranes, proteins and DNA and thus may trigger the onset of disease. These small inorganic molecules react independently as well as in a concerted manner to mediate physiological responses. This review provides a general overview of the redox biology of these key molecules, their diverse chemistry relevant to physiological processes and their interrelated nature in cellular signaling. Show less

Various intrinsic factors, including the metabolic state of cancer cells, govern their ability to evade immune destruction. Here the authors show that inactivation of dihydroorotate dehydrogenase (DHODH), an enzyme in the pyrimidine synthesis pathway, increases the sensitivity of cancer cells to T cell cytotoxicity through CDP-Choline dependent induction of ferroptosis. Show less

The aim of the UniProt Knowledgebase (UniProtKB; https://www.uniprot.org/) is to provide users with a comprehensive, high-quality and freely accessible set of protein sequences annotated with functional information. In this publication, we describe ongoing changes to our production pipeline to limit the sequences available in UniProtKB to high-quality, non-redundant reference proteomes. We continue to manually curate the scientific literature to add the latest functional data and use machine learning techniques. We also encourage community curation to ensure key publications are not missed. We provide an update on the automatic annotation methods used by UniProtKB to predict information for unreviewed entries describing unstudied proteins. Finally, updates to the UniProt website are described, including a new tab linking protein to genomic information. In recognition of its value to the scientific community, the UniProt database has been awarded Global Core Biodata Resource status. Show less

This study is dedicated to the development of multimodal anticancer agents. We have obtained ruthenium complexes conjugated with the steroid-type antitumor drug abiraterone acetate in order to take advantage of the dual antitumor properties of both ruthenium and abiraterone. The compounds exhibit good antiproliferative activity against cancer cells, with selectivity over primary fibroblasts. Real-time cell analysis revealed that compound dichlorido(η⁶-p-cymene)(abiraterone acetate)ruthenium(II) had pronounced antiproliferation activity compared to abiraterone acetate. Flow cytometric studies on the mechanism of cell death have revealed that the most active compound induces apoptosis more effectively than abiraterone acetate. Our findings demonstrate the potential of this novel dual-action compound as promising candidates for further development as anticancer agents. Show less

Overweight and obesity are a worldwide common problem and are diagnosed with a body mass index (BMI) value in the range of 25.0-29.9 kg/m2 and ≥30.0 kg/m2, respectively. Obese patients are at high risk of developing concomitant diseases, such as hypertension, type 2 diabetes mellitus (DM2), hyperlipidemia, stroke and even some types of cancer. In the Russian Federation in 2016, the proportion of overweight people was 62.0%, with obesity - 26.2%. The authors performed an electronic search in the PubMed information database. Two search elements were used: «Semaglutide» and «Obesity». The search included studies published from the date of foundation of the database to August 2022. The search was limited only to the results of clinical trials. The authors obtained 26 results, but only the studies of SUSTAIN, PIONEER (Peptide Innovation for Early Diabetes Treatment) and STEP were considered, since they were original, randomized, controlled clinical trials conducted before the approval of semaglutide for the treatment of DM2 and obesity. Show less

The combination of one molecule of organic and metal-based fragments that exhibit antitumor activity is a modern approach in the search for new promising drugs. In this work, biologically active ligands based on lonidamine (a selective inhibitor of aerobic glycolysis used in clinical practice) were introduced into the structure of an antitumor organometallic ruthenium scaffold. Resistant to ligand exchange reactions, compounds were prepared by replacing labile ligands with stable ones. Moreover, cationic complexes containing two lonidamine-based ligands were obtained. Antiproliferative activity was studied in vitro by MTT assays. It was shown that the increase in the stability in ligand exchange reactions does not influence cytotoxicity. At the same time, the introduction of the second lonidamine fragment approximately doubles the cytotoxicity of studied complexes. The ability to induce apoptosis and caspase activation in tumour cell MCF7 was studied by employing flow cytometry. Show less

Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit. Show less

Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not, administration of antioxidants is ineffective, suggesting that our current understanding of the underlying regulatory processes is incomplete. Recent Advances: Similar to reactive oxygen species and reactive nitrogen species, reactive sulfur species are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism, and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept defined as the reactive species interactome (RSI). The RSI is a primeval multilevel redox regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stressors to enhance fitness and resilience at the local and whole-organism level. Show less

We report on the synthesis of novel Ru(II) compounds (Ru-1 to Ru-8) bearing R-pdc, 4-Cl-pbinh ligands (where R=4-CF3, 4-F, 4-OH pdc=3-phenyl-5-(1H-pyrrol-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide, pbinh=phenoxybenzylidene isonicotinyl hydrazides) and their in vitro antitumor activity toward the cell lines murine leukemia L1210, human lymphocyte CEM, human epithelial cervical carcinoma HeLa, BEL-7402 and Molt4/C8. Some of the complexes exhibited more potent antiproliferative activity against cell lines than the standard drug cisplatin. Ruthenium complex Ru-2 displayed potent cytotoxicity with than that of cisplatin. DNA-binding, DNA cleavage and protein binding properties of ruthenium complexes with these ligands are reported. Interactions of these ruthenium complexes with DNA revealed an intercalative mode of binding between them. Synchronous fluorescence spectra proved that the interaction of ruthenium complexes with bovine serum albumin (BSA) resulted in a conformational change of the latter. Show less

Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards understanding the molecular basis of RNA polymerase II (Pol II) transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. In particular, we will focus on the three key checkpoint steps of controlling Pol II transcriptional fidelity: insertion (specific nucleotide selection and incorporation), extension (differentiation of RNA transcript extension of a matched over mismatched 3'-RNA terminus), and proofreading (preferential removal of misincorporated nucleotides from the 3'-RNA end). We will also discuss some novel insights into the molecular basis and chemical perspectives of controlling Pol II transcriptional fidelity through structural, computational, and chemical biology approaches. Show less