Specific Biological Targets Research Articles

Is it Time for Multi-Drug Therapy with Combination of Therapeutic Nucleic Acids?

Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs.

Applications of Biological Therapy for Latent Infections: Benefits and Risks.

Biological therapies have revolutionized medical treatment by targeting the key mediators or receptors involved in inflammatory responses, thereby effectively suppressing inflammation and achieving beneficial outcomes. They are more advanced than conventional therapies using corticosteroids and immunosuppressants, offering effective solutions for autoimmune diseases, cancer, transplant rejection, and various infectious diseases, including coronavirus disease 2019. Although they exert low immunosuppressive effects, biological therapies can reactivate specific biological targets associated with infections. This review summarizes the currently available biological therapies and discusses their immunosuppressive mechanisms and clinical applications, highlighting the variations in the types and frequencies of infection recurrence induced by different biological agents. Additionally, this review describes the risk factors associated with various biological agents, thus aiding clinicians in selecting the most appropriate biological therapy.

Pharmacological potential of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides

The discovery of new 1,2,4-triazole derivatives offers significant potential for the development of innovative medications. Researchers often favor derivatives of this heterocyclic system due to their ability to create chemical structures with desired pharmacokinetic and pharmacodynamic properties, allowing for targeted effects on specific biological targets. Importantly, biologically active compounds containing triazole have demonstrated relatively low toxicity and minimal risks of mutagenicity. The synergistic combination of these characteristics provides favorable conditions for the development of complex therapeutic effects, ultimately leading to the creation of novel biologically active substances and offering new avenues for the effective treatment of various diseases. Indeed, the utilization of a diverse array of chemical transformations and functionalizations is crucial for obtaining bioactive molecules with desired properties. In this context, 1,2,4-triazole and its derivatives offer a platform for executing a comprehensive range of chemical transformations, thereby enabling the development of compounds with enhanced pharmacokinetic and pharmacodynamic parameters. The aim of the study was to preliminarily assess the possibility of creating a biologically active substance based on 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-R-1,2,4-triazole halides. Materials and methods. In silico analysis was used to assess the safety and potential toxicity of the presented compounds, which was implemented using the T.E.S.T. software developed by the US Environmental Protection Agency. SwissADME is an online resource as an effective tool for studying the physicochemical properties and pharmacokinetic parameters of the compounds proposed for study. A molecular docking method that uses a variety of computational algorithms to predict and analyze interactions, including determining the presence of possible binding sites, estimating binding energies, and the spatial arrangement of molecules. The ligand models were created using MarvinSketch 6.3.0, Hyper Chem 8, and AutoDockTools-1.5.6. Discovery Studio 4.0 and AutoDockTools-1.5.6 have been used to prepare the enzymes for analysis. For direct molecular docking, Vina software has been used, which allows predicting and evaluating the interaction between the ligand molecule and the three-dimensional structure of the target protein, taking into account their energy and spatial compatibility. Results. A virtual set of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides was prescreened, which are potential candidates for the further synthesis of biologically active compounds. The general level of toxicity and harmlessness was determined at the predictive level. The key physicochemical characteristics of the molecules have been determined and the general pharmacokinetic parameters have been identified, which allows for a better understanding of their interaction and behavior in the body. The active sites of the model enzymes were analyzed using Vina software, which contributes to a deeper understanding of the interaction of enzymes with their substrates. According to the results of the study, an increased probability of the formation of anti-inflammatory and anticancer properties occurs in 1-alkyl derivatives of 3,5-dimethyl-4-(3-((5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides with an odd number of Сarbon atoms. Instead, the highest affinity for lanosterol 14α-demethylase has been demonstrated in the studied derivatives with octyl and nonyl substituents, which shows a certain probability of antifungal activity. Conclusions. The prognosis for the creation of a biologically active substance using 1-alkyl derivatives of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides is quite favorable.

Optofluidic photonic crystal fiber platform for sensitive and reliable fluorescence based biosensing.

Biosensing plays a pivotal role in various scientific domains, offering significant contributions to medical diagnostics, environmental monitoring, and biotechnology. Fluorescence biosensing relies on the fluorescence emission from labelled biomolecules to enable sensitive and selective identification and quantification of specific biological targets in various samples. Photonic crystal fibers (PCFs) have led to the development of optofluidic fibers enabling efficient light-liquid interaction within small liquid volume. Herein, we present the development of a user-friendly optofluidic-fiber platform with simple hardware requirements for sensitive and reliable fluorescence biosensing with high measurement repeatability. We demonstrate a sensitivity improvement of the fluorescence emission up to 17 times compared to standard cuvette measurement, with a limit of detection of Cy5 fluorophore as low as 100 pM. The improvement in measurement repeatability is exploited for detecting haptoglobin protein, a relevant biomarker to diagnose several diseases, by using commercially available Cy5 labelled antibodies. The study aims to showcase an optofluidic platform leveraging the benefits provided by optofluidic fibers, which encompass easy light injection, robustness, and high sensitivity.

Proteomics analysis on aortic smooth muscle cells reveals new potential targets for the treatment of Marfan syndrome-associated thoracic aortic aneurysm

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health Background Thoracic aortic aneurysm (TAA) is characterized by the abnormal enlargement of the initial segment of the aorta. Patients with genetic Marfan syndrome (MFS) develop TAA in young age, since mutations of fibrillin-1 contribute to thoracic aortic wall detrimental weakening. Presently, effective treatment options for this life-threatening condition are lacking, and existing pharmacological approaches are merely palliative, by postponing the need for surgical aortic replacement. To identify new treatments or MFS-related TAA (MFS-TAA), current research is concentrated on pinpointing specific biological targets and mechanisms underlying this aortic disorder. Purpose This study is aimed to unveil potential therapeutic targets that could be exploited for treating MFS-TAA by adopting an advanced proteomics technique. Material and Methods A label-free quantitative mass spectrometry technique was employed, utilizing a hybrid quadrupole-time of flight mass spectrometer coupled with a UPLC Mclass system and a nano-source, to analyze and compare the protein expression levels in vascular smooth muscle cells (VSMC) isolated from the aortas of MFS patients (MFS-VSMC) and healthy subjects (HC-VSMC). The proteomics findings were subsequently validated through qRT-PCR and Western blot assays. Results The proteomics investigation yielded 16 proteins displaying statistically significant differences. Among these, five proteins were notably more abundant in MFS-VSMC compared to HC-VSMC: nestin (NES, p<0.01), filamin B (FLNB, p<0.05), A-kinase anchor protein 12 (AKAP12, p<0.05), catenin delta-1 (CTNND1, p<0.05), and heparan sulfate proteoglycan core protein (HSPG2, p<0.05). The Gene Ontology (GO) analysis performed on cellular components of these 5 items using the clusterProfiler R package highlighted the enrichment of GO terms generally related to transmembrane proteins and anchoring junctions. Specifically, enriched GO terms included cell cortex (p<0.002), focal adhesion (p<0.002), cell-substrate junction (p<0.002), and intermediate filament binding (p<0.03). To verify these findings, two out of the five proteins with increased expression in MFS-VSMC (i.e., nestin and filamin B) were subjected to validation experiments. Results confirmed the elevated gene expression and protein levels of both nestin (p<0.05) and filamin B (p<0.05) in MFS-VSMC samples when compared with HC-VSMC. Conclusions Taken together, these results suggest that proteins with increased expression in MFS-VSMC may represent valuable biological target of MFS-TAA. This may encompass their potential both as diagnostic tools and/or mechanistic mediators of TAA in MFS subjects. In details, the pharmacological targeting of nestin and filamin B may represent a novel and exploitable therapeutic option for limiting/inhibiting TAA onset or progression in MFS pathological scenario.

ChemFH: an integrated tool for screening frequent false positives in chemical biology and drug discovery.

High-throughput screening rapidly tests an extensive array of chemical compounds to identify hit compounds for specific biological targets in drug discovery. However, false-positive results disrupt hit compound screening, leading to wastage of time and resources. To address this, we propose ChemFH, an integrated online platform facilitating rapid virtual evaluation of potential false positives, including colloidal aggregators, spectroscopic interference compounds, firefly luciferase inhibitors, chemical reactive compounds, promiscuous compounds, and other assay interferences. By leveraging a dataset containing 823391 compounds, we constructed high-quality prediction models using multi-task directed message-passing network (DMPNN) architectures combining uncertainty estimation, yielding an average AUC value of 0.91. Furthermore, ChemFH incorporated 1441 representative alert substructures derived from the collected data and ten commonly used frequent hitter screening rules. ChemFH was validated with an external set of 75 compounds. Subsequently, the virtual screening capability of ChemFH was successfully confirmed through its application to five virtual screening libraries. Furthermore, ChemFH underwent additional validation on two natural products and FDA-approved drugs, yielding reliable and accurate results. ChemFH is a comprehensive, reliable, and computationally efficient screening pipeline that facilitates the identification of true positive results in assays, contributing to enhanced efficiency and success rates in drug discovery. ChemFH is freely available via https://chemfh.scbdd.com/.

Revealing an adverse outcome pathway network for reproductive toxicity induced by atrazine, via oxidative stress

Adverse outcome pathway AOPs are conceptual frameworks that organize scientific knowledge about how stressors disrupt specific biological targets, pathways. AOP network consists of two or more AOPs that share common key events (KEs), including crucial events like molecular initiating events (MIEs) and adverse outcomes (AOs), which offer the opportunity to link toxicological pathways. Thus, to better understand the sequential series of KEs involved in the AOP 492 (https://aopwiki.org/aops/492), which is triggered by atrazine (ATZ), we first generated a Reproductive Toxicity via Oxidative Stress (RTOS) AOP network from individual AOPs published in the AOP-Wiki database, using this AOP as a seed. The KEs “Increased, Reactive oxygen species” and “Apoptosis” were considered the most common/highly connected KE within this network and an important point of divergence. Furthermore, “Increased, DNA damage and mutations” is a critical KE within the network, as it is highly connected and central, and represents a point of divergence. This suggests that these three KEs have a high predictive value and could, for example, serve as a basis for the development/selection of in vitro assays to assess reproductive toxicity. The in silico analyses revealed that the pivotal target proteins for ATZ-induced infertility via oxidative stress in humans are Tp53, Bcl2, Esr1, and Nos3, which interact indirectly with ATZ via intermediary factors such as Mapk3, Mapk1, and Cyp19a1. Further, the gene enrichment analyses indicate that these entities are involved in several biological processes and pathways directly associated with oxidative stress, DNA damage and apoptosis, further reinforcing the developed network.

Abstract 3001: Multiomics Analysis On Ascending Aorta Reveals New Potential Targets Of Marfan Syndrome-associated Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) is defined as the pathological enlargement of the first aortic trait. Patients with genetic Marfan syndrome (MFS) develop TAA in young age, since mutations of fibrillin-1 contribute to aortic wall detrimental weakening. To date, effective treatment options for this life-threatening condition are lacking, and pharmacological approaches are merely palliative, postponing the surgical aortic replacement. To identify new treatments for MFS-related TAA (MFS-TAA), current research is concentrated on pinpointing specific biological targets and mechanisms underlying this aortic disorder. Aim of this study is to unveil new specific and potential targets of MFS-TAA. Spatial transcriptomics was performed on healthy subject and MFS patients’ thoracic aortas, whereas protein expression levels of vascular smooth muscle cells from MFS patients’ (MFS-VSMC) and healthy subjects (HC-VSMC) were analyzed by quantitative mass spectrometry. -Omics results were validated by qRT-PCR and Western blot assays. Spatial transcriptomic results revealed 2 different cell clusters in the aortic tunicae , best representing aortic VSMC. Structural proteins ( e.g. , NES , DES , CNN1 ), were the most transcribed genes in MFS-TAA in comparison with HC aorta. Notably, proteomics yielded five proteins, statistically more abundant in MFS-VSMC vs. HC-VSMC (p<0.05): nestin, filamin B, A-kinase anchor protein 12, catenin delta-1, and heparan sulfate proteoglycan core protein. The Gene Ontology (GO) analysis performed on cellular components of both transcripts and proteins more expressed in MFS aortic samples highlighted the enrichment of GO terms related to extracellular compartment, actin and cytoskeleton components, and cell adhesion. We validated the levels of nestin, which increased expression in MFS specimens has been observed by both -omics techniques. The results of validation experiments confirmed higher nestin gene expression and protein levels in MFS-VSMC samples (p<0.05) when compared with HC-VSMC. Results suggest a valuable biological target role for nestin, which pharmacological targeting may represent, in the future, a novel and exploitable therapeutic option for limiting/inhibiting TAA onset or progression in MFS scenario.

SwissDock 2024: major enhancements for small-molecule docking with Attracting Cavities and AutoDock Vina.

Drug discovery aims to identify potential therapeutic compounds capable of modulating the activity of specific biological targets. Molecular docking can efficiently support this process by predicting binding interactions between small molecules and macromolecular targets and potentially accelerating screening campaigns. SwissDock is a computational tool released in 2011 as part of the SwissDrugDesign project, providing a free web-based service for small-molecule docking after automatized preparation of ligands and targets. Here, we present the latest version of SwissDock, in which EADock DSS has been replaced by two state-of-the-art docking programs, i.e. Attracting Cavities and AutoDock Vina. AutoDock Vina provides faster docking predictions, while Attracting Cavities offers more accurate results. Ligands can be imported in various ways, including as files, SMILES notationor molecular sketches. Targets can be imported as PDB files or identified by their PDB ID. In addition, advanced search options are available both for ligands and targets, giving users automatized access to widely-used databases. The web interface has been completely redesigned for interactive submission and analysis of docking results. Moreover, we developed a user-friendly command-line access which, in addition to all options of the web site, also enables covalent ligand docking with Attracting Cavities. The new version of SwissDock is freely available at https://www.swissdock.ch/.

Photochemical Degradation of the New Nicotine Pesticide Acetamiprid in Water.

Acetamiprid is a novel nicotinic pesticide widely used in modern agriculture because of its low toxicity and specific biological target properties. The objective of this study was to understand the photolysis pattern of acetamiprid in the water column and elucidate its degradation products and mechanism. It was observed that acetamiprid exhibited different photolysis rates under different light source conditions in pure water, with ultraviolet > fluorescence > sunlight; furthermore, its photolysis half-life ranged from 17.3 to 28.6h. In addition, alkaline conditions (pH 9.0) accelerated its photolysis rate, which increased with pH. Using gas chromatography-mass spectrometry, five direct photolysis products generated during the exposure of acetamiprid to pure water were successfully separated and identified. The molecular structure of acetamiprid was further analyzed using density functional theory, and the active photodegradation sites of acetamiprid were predicted. The mechanism of the photolytic transformation of acetamiprid in water was mainly related to hydroxyl substitution and oxidation. Based on these findings, a comprehensive transformation pathway for acetamiprid was proposed.

High-Throughput GPCRome Screen of Pollutants Reveals the Activity of Polychlorinated Biphenyls at Melatonin and Sphingosine-1-phosphate Receptors.

Exposure to environmental pollutants is linked to numerous toxic outcomes, warranting concern about the effect of pollutants on human health. To assess the threat of pollutant exposure, it is essential to understand their biological activity. Unfortunately, gaps remain for many pollutants' specific biological activity and molecular targets. A superfamily of signaling proteins, G-protein-coupled receptors (GPCRs), has been shown as potential targets for pollutant activity. However, research investigating the pollutant activity at the GPCRome is scarce. This work explores pollutant activity across a library of human GPCRs by leveraging modern high-throughput screening techniques devised for drug discovery and pharmacology. We designed and implemented a pilot screen of eight pollutants at 314 human GPCRs and discovered specific polychlorinated biphenyl (PCB) activity at sphingosine-1-phosphate and melatonin receptors. The method utilizes open-source resources available to academic and governmental institutions to enable future campaigns that screen large numbers of pollutants. Thus, we present a novel high-throughput approach to assess the biological activity and specific targets of pollutants.

Artificial Intelligence and Machine Learning Methods to Evaluate Cardiotoxicity following the Adverse Outcome Pathway Frameworks.

Cardiovascular disease is a leading global cause of mortality. The potential cardiotoxic effects of chemicals from different classes, such as environmental contaminants, pesticides, and drugs can significantly contribute to effects on health. The same chemical can induce cardiotoxicity in different ways, following various Adverse Outcome Pathways (AOPs). In addition, the potential synergistic effects between chemicals further complicate the issue. In silico methods have become essential for tackling the problem from different perspectives, reducing the need for traditional in vivo testing, and saving valuable resources in terms of time and money. Artificial intelligence (AI) and machine learning (ML) are among today's advanced approaches for evaluating chemical hazards. They can serve, for instance, as a first-tier component of Integrated Approaches to Testing and Assessment (IATA). This study employed ML and AI to assess interactions between chemicals and specific biological targets within the AOP networks for cardiotoxicity, starting with molecular initiating events (MIEs) and progressing through key events (KEs). We explored methods to encode chemical information in a suitable way for ML and AI. We started with commonly used approaches in Quantitative Structure-Activity Relationship (QSAR) methods, such as molecular descriptors and different types of fingerprint. We then increased the complexity of encoders, incorporating graph-based methods, auto-encoders, and character embeddings employed in neural language processing. We also developed a multimodal neural network architecture, capable of considering the complementary nature of different chemical representations simultaneously. The potential of this approach, compared to more conventional architectures designed to handle a single encoder, becomes apparent when the amount of data increases.

Bioactive agents from Parkia biglobosa (Jacq.) R.Br. ex G. Don bark extracts for health promotion and nutraceutical uses.

Parkia biglobosa stem bark extracts were prepared using methanol, methanol 80%, water and ethyl acetate to investigate their phytochemical contents, as well as antioxidant and enzyme inhibitory properties. Liquid chromatography (LC) quadrupole time-of-flight mass spectrometry (MS) and LC-MSn revealed the presence of flavonoids, hydroxycinnamic acid derivatives and gallotannins. Particularly, the water extract contained rutin (480 μg per 100 mg) and 3-caffeoylquinic acid (1109 μg per 100 mg) in higher amounts, whereas the 80% methanol extract contains methoxyluteolin-7-O-rutinoside and catechin derivatives as major compounds. Total phenolic and flavonoid contents of the extracts were yielded in the range of 32.26-119.88 mg gallic acid equivalents g-1 and 0.60-2.39 mg rutin equivalents g-1 , respectively. Total antioxidant capacity was also displayed in the range of 0.53-6.34 mmol Trolox equivalents (TE) g-1 . Both the methanolic extracts showed higher total antioxidant capacity that could be related to the total phenolic contents. Radical scavenging capacity in DPPH (2,2-diphenyl-2-picryl-hydrazyl) (37.21-508.30 mg TE g-1 ) and ABTS [2,2-azinobis(3-ethylbenzothiazoline- 6-sulfonic acid)] (60.95-1068.06 mg TE g-1 ) assays, reducing power in cupric ion reducing antioxidant capacity (54.23-1002.78 mg TE g-1 ) and ferric ion reducing antioxidant power (33.18-558.68 mg TE g-1 ) assays, as well as metal chelating activity (2.45-11.28 mg EDTA equivalents g-1 ), were exhibited by all extracts. All extracts were found to inhibit acetylcholinesterase [0.23-2.47 mg galanthamine equivalents (GALAE) g-1 ], tyrosinase [27.20-83.33 mg kojic acid equivalents g-1 ], amylase [mmol acarbose equivalents (ACAE) g-1 ]. On the other hand, all extracts, except the water extract, inhibited butyrylcholinesterase (5.38-6.56 mg GALAE g-1 ), whereas only the water and ethyl acetate extract showed glucosidase inhibitory potential (1.96 and 1.82 mmol ACAE g-1 ). In general, the water extract was found to be a weaker enzyme inhibitor suggesting that water is not the preferrable extraction solvent to obtain active products. The present study demonstrated that the stem bark extracts of P. biglobosa contains good amount of phytochemical and extracts present significant antioxidant, as well as reasonable enzyme inhibitory effects. Hence, these findings suggest that further studies can be performed on more specific biological targets and models of bioactivity to determine their safe usage as a nutraceutical or for the preparation functional foods. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Chemical and biological versatility of pyrazolo[3,4-d]pyrimidines: one scaffold, multiple modes of action.

Plain language summary Pyrazolo[3,4-d]pyrimidines are chemical compounds possessing remarkable versatility and significance in both biological and chemical contexts. These compounds are composed of specific arrangements of atoms, forming a unique ring structure, which is able to form bonds in a similar way as purines do. In the realm of chemistry, pyrazolo[3,4-d]pyrimidines showcase impressive flexibility due to their ability to easily react with various molecules, opening avenues for the creation of novel compounds with diverse properties for potential applications in medicinal chemistry. In a biological context, pyrazolo[3,4-d]pyrimidines play a crucial role due to their interaction with proteins such as enzymes. In fact, these compounds can impact various biological processes, including cancer cell proliferation, oxidative stress and inflammation. This has led to investigations into their potential as therapeutic agents: by designing pyrazolo[3,4-d]pyrimidines with specific biological targets in mind, new drugs can be developed for the effective treatment of a range of medical conditions. Finally, novel administration tools (e.g., nanomaterials and functionalized liposomes) are being studied as effective ways to overcome the main unwanted characteristics of pyrazolo[3,4-d]pyrimidines (scarce solubility and off-target side effects), thereby increasing their efficacy and specificity toward cell targets. In conclusion, pyrazolo[3,4-d]pyrimidines are fascinating molecules with a dual role in chemistry and biology. Their adaptability in chemical reactions makes them valuable building blocks for designing new compounds with diverse applications. Additionally, their interaction with biological molecules holds promise for the development of innovative medicines. Ongoing research into the properties and behaviors of these compounds could lead to significant advancements in both scientific fields.

Mechanistic insights on anticancer drugs with specific biological targets and signalling pathways

Mechanistic insights on anticancer drugs with specific biological targets and signalling pathways

Phthalocyanine aggregates in the photodynamic therapy: dogmas, controversies, and future prospects.

Photodynamic therapy (PDT), a rapidly developing method for the treatment of cancer and bacterial diseases, is based on the photosensitization of oxygen to generate reactive oxygen species (ROS) that destroy specific biological targets. Among the various photosensitizers, phthalocyanines (Pc) have attracted particular attention due to their excellent photophysical properties, most of which meet the therapeutic requirements. The statement that aggregation of Pc-based photosensitizers is undesirable because it suppresses ROS generation has become commonplace in PDT. In this review, we have collected and discussed a number of works whose results refute this well-established axiom and show that aggregated forms of phthalocyanines can still exhibit photodynamic activity, in some cases in synergy with the photothermal and optoacoustic effects. In addition, ROS generation can be induced by aggregates under the conditions of sonodynamic therapy.

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This study explores eco‐friendly wearable/implantable bioelectronics for next‐generation smart healthcare, tailored to specific biological targets. We discuss target‐specific considerations and key parameters of these bioelectronic systems.To illustrate our approach, the cover showcases an integrated system of bioelectronic chips with holographic representations of each target organ. Furthermore, we demonstrate real‐time brain monitoring as an example of target‐tailored smart healthcare. image

FSM-DDTR: End-to-end feedback strategy for multi-objective De Novo drug design using transformers

The design of compounds that target specific biological functions with relevant selectivity is critical in the context of drug discovery, especially due to the polypharmacological nature of most existing drug molecules. In recent years, in silico-based methods combined with deep learning have shown promising results in the de novo drug design challenge, leading to potential leads for biologically interesting targets. However, several of these methods overlook the importance of certain properties, such as validity rate and target selectivity, or simplify the generative process by neglecting the multi-objective nature of the pharmacological space. In this study, we propose a multi-objective Transformer-based architecture to generate drug candidates with desired molecular properties and increased selectivity toward a specific biological target. The framework consists of a Transformer-Decoder Generator that generates novel and valid compounds in the SMILES format notation, a Transformer-Encoder Predictor that estimates the binding affinity toward the biological target, and a feedback loop combined with a multi-objective optimization strategy to rank the generated molecules and condition the generating distribution around the targeted properties. The results demonstrate that the proposed architecture can generate novel and synthesizable small compounds with desired pharmacological properties toward a biologically relevant target. The unbiased Transformer-based Generator achieved superior performance in the novelty rate (97.38%) and comparable performance in terms of internal diversity, uniqueness, and validity against state-of-the-art baselines. The optimization of the unbiased Transformer-based Generator resulted in the generation of molecules exhibiting high binding affinity toward the Adenosine A2A Receptor (AA2AR) and possessing desirable physicochemical properties, where 99.36% of the generated molecules follow Lipinski’s rule of five. Furthermore, the implementation of a feedback strategy, in conjunction with a multi-objective algorithm, effectively shifted the distribution of the generated molecules toward optimal values of molecular weight, molecular lipophilicity, topological polar surface area, synthetic accessibility score, and quantitative estimate of drug-likeness, without the necessity of prior training sets comprising molecules endowed with pharmacological properties of interest. Overall, this research study validates the applicability of a Transformer-based architecture in the context of drug design, capable of exploring the vast chemical representation space to generate novel molecules with improved pharmacological properties and target selectivity. The data and source code used in this study are available at: https://github.com/larngroup/FSM-DDTR.

Lighting-Up the Far-Red Fluorescence of RNA-Selective Dyes by Switching from Ortho to Para Position

Fluorescence imaging is constantly searching for new far-red emitting probes whose turn-on response is selective upon the interaction with specific biological targets. Cationic push-pull dyes could indeed respond to these requirements due to their intramolecular charge transfer (ICT) character, by which their optical properties can be tuned, and their ability to interact strongly with nucleic acids. Starting from the intriguing results recently achieved with some push-pull dimethylamino-phenyl dyes, two isomers obtained by switching the cationic electron acceptor head (either a methylpyridinium or a methylquinolinium) from the ortho to the para position have been scrutinized for their ICT dynamics, their affinity towards DNA and RNA, and in vitro behavior. By exploiting the marked fluorescence enhancement observed upon complexation with polynucleotides, fluorimetric titrations were employed to evaluate the dyes' ability as efficient DNA/RNA binders. The studied compounds exhibited in vitro RNA-selectivity by localizing in the RNA-rich nucleoli and within the mitochondria, as demonstrated by fluorescence microscopy. The para-quinolinium derivative showed some modest antiproliferative effect on two tumor cell lines as well as improved properties as an RNA-selective far-red probe in terms of both turn-on response (100-fold fluorescence enhancement) and localized staining ability, attracting interest as a potential theranostic agent.

An Understanding of Mechanism-Based Approaches for 1,3,4-Oxadiazole Scaffolds as Cytotoxic Agents and Enzyme Inhibitors.

The world's health system is plagued by cancer and a worldwide effort is underway to find new drugs to treat cancer. There has been a significant improvement in understanding the pathogenesis of cancer, but it remains one of the leading causes of death. The imperative 1,3,4-oxadiazole scaffold possesses a wide variety of biological activities, particularly for cancer treatment. In the development of novel 1,3,4-oxadiazole-based drugs, structural modifications are important to ensure high cytotoxicity towards malignant cells. These structural modification strategies have shown promising results when combined with outstanding oxadiazole scaffolds, which selectively interact with nucleic acids, enzymes, and globular proteins. A variety of mechanisms, such as the inhibition of growth factors, enzymes, and kinases, contribute to their antiproliferative effects. The activity of different 1,3,4-oxadiazole conjugates were tested on the different cell lines of different types of cancer. It is demonstrated that 1,3,4-oxadiazole hybridization with other anticancer pharmacophores have different mechanisms of action by targeting various enzymes (thymidylate synthase, HDAC, topoisomerase II, telomerase, thymidine phosphorylase) and many of the proteins that contribute to cancer cell proliferation. The focus of this review is to highlight the anticancer potential, molecular docking, and SAR studies of 1,3,4-oxadiazole derivatives by inhibiting specific cancer biological targets, such as inhibiting telomerase activity, HDAC, thymidylate synthase, and the thymidine phosphorylase enzyme. The purpose of this review is to summarize recent developments and discoveries in the field of anticancer drugs using 1,3,4-oxadiazoles.