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Exploiting cheminformatic and machine learning to navigate the available chemical space of potential small molecule inhibitors of SARS-CoV-2.

The current life-threatening and tenacious pandemic eruption of coronavirus disease in 2019 (COVID-19) has posed a significant global hazard concerning high mortality rate, economic meltdown, and everyday life distress. The rapid spread of COVID-19 demands countermeasures to combat this deadly virus. Currently, there are no drugs approved by the FDA to treat COVID-19. Therefore, discovering small molecule therapeutics for treating COVID-19 infection is essential. So far, only a few small molecule inhibitors are reported for coronaviruses. There is a need to expand the small chemical space of c

Survival of heparins, oral anticoagulants, and aspirin after the year 2010.

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants, and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. The development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will ever match the polypharmacology of heparin. Aspir…

Heparin, low-molecular-weight heparins, and heparin pentasaccharide: basic and clinical differentiation.

As a result of advanced technology, dramatic developments in the area of new anticoagulant and antithrombotic drugs appear to have made a profound impact on the use of LMWHs. Furthermore, because porcine mucosal heparin is used for the preparation of these agents, it is likely that alternative drugs with comparable pharmacologic and clinical efficacy are sought. Antithrombin drugs such as argatroban and hirudin are already approved for alternative management of heparin-compromised patients. Their efficacy in other indications is less superior. The development of specific anti-Xa drugs is slow.

[Novel approach to respiratory pharmacology--pharmacological basis of cough, sputum and airway clearance].

Disturbance of the normal mucociliary clearance due to hyperproduction of mucus and modification of its physicochemical characteristics is a common finding in airway diseases. Drugs that affect airway secretion have been developed and used to cleanse the respiratory tract for many centuries and in many countries. On the basis of the mechanism of their actions, the mucoactive drugs are classified into several groups. Some mucoactive drugs have direct effects on the production or composition of airway secretions, resulting in increased effectiveness of mucociliary clearance. Other mucoactive dru

Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry.

Many of the drugs used in treatment today have been designed based on the "specificity paradigm". Resistance has developed against drugs designed using this approach, leading to a decrease in their effectiveness. In addition, it is well-documented in the literature that diseases with complex etiologies, such as Alzheimer's, Parkinson's, and cancer are influenced by multiple genetic and/or environmental factors. As a result, specificity paradigm is often insufficient for treating these diseases. Therefore, there is a need to develop drugs that interact with multiple targets simultaneously throu

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… In support of the growing interest in multitarget strategies, recent drug approval trends also reflect a shift toward polypharmacology. … In Germany, ≈20% of newly approved drugs are classified as multitarget therapies, either as fixed‐dose combinations or as agents with well‐defined polypharmacological profiles. [ 8 ] This trend reflects an increasing recognition of polypharmacology as a viable and effective approach for treating complex …

Artificial intelligence in drug discovery and development.

Artificial intelligence-integrated drug discovery and development has accelerated the growth of the pharmaceutical sector, leading to a revolutionary change in the pharma industry. Here, we discuss areas of integration, tools, and techniques utilized in enforcing AI, ongoing challenges, and ways to overcome them.

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… AI can be used effectively in different parts of drug discovery, including drug design, chemical synthesis, drug screening, polypharmacology, and drug repurposing. … Polypharmacology: drug discovery for the future Expert Rev. Clin. Pharmacol. 6 2013 41 47 23272792 10.1586/ecp.12.74 PMC3809828 71 Li Z. …

Роль окситоцина и Васопрессина в нейропсихиатрических расстройствах: терапевтический потенциал агонистов и антагонистов.

Окситоцин (OT) и вазопрессин (AVP) являются гипоталамическими нейропептидами, которые традиционно ассоциируются с их регулирующей ролью в размножении, гомеостазисе воды и социальном поведении. Интересно, что в последние годы эта роль расширилась и эти нейропептиды стали лечебными мишенями для различных нейропсихиатрических заболеваний, таких, как аутизм, зависимость, шизофрения, депрессия и тревожное расстройство. В связи с химическими и физическими характеристиками этих нейропептидов, включая короткий период полураспада, плохое проникновение через мозговые барьеры, беспорядочность для AVP и O

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… This has led to the development of the concept of polypharmacology, which refers to the ability of a molecule to simultaneously interact with multiple target proteins or receptors [ 215 ]. … In this context, OT-R and AVP-R appear as exceptionally attractive targets for CNS polypharmacology. …

Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer.

The strategy of using existing drugs originally developed for one disease to treat other indications has found success across medical fields. Such drug repurposing promises faster access of drugs to patients while reducing costs in the long and difficult process of drug development. However, the number of existing drugs and diseases, together with the heterogeneity of patients and diseases, notably including cancers, can make repurposing time consuming and inefficient. The key question we address is how to efficiently repurpose an existing drug to treat a given indication. As drug efficacy rem

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… Although they have been greatly improved to have potent selectivity, many have additional effects on other kinases and beyond their target family [ 21 , 22 ], thus displaying an intrinsic polypharmacology often favorable for their clinical efficacy [ 23 ]. … For it to be generally successful, a polypharmacological repurposing approach needs the systematic integration of the scientific data derived from different drug discovery and mechanistic disciplines. …

The Advent of Molecular Targeted Therapies Against Cancer. Toward Multi-Targeting Drugs Through Materials Engineering: A Possible Future Scenario.

The authors, actively engaged in the development of mesoporous silica-based solutions, initially for modified drug release, later for the smart administration of conventional chemotherapeutic cytotoxic drugs, present the evolution of the concept of targeted therapy across different disciplines. They also discuss the diverse therapeutic needs and related challenges (adverse drug effects) that have unfolded over the last 30 years. Nanomedicine potentialities, mainly against cancers, that have emerged globally during the intense research activity of the last few decades, are critically discussed.

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… The ability of a molecule to bind to multiple proteins within a disease pathway is referred to as “promiscuity”, and it constitutes a key feature for a molecule to be considered a polypharmacologic drug candidate. Unfortunately, promiscuity is not always easily related to molecular features. … However, in the context of this specific article and its focus, we propose a polypharmacology approach to develop a purely molecular multitargeting therapy, devoid of immunological elements. …

Some Aspects and Convergence of Human and Veterinary Drug Repositioning.

Drug innovation traditionally follows a de novo approach with new molecules through a complex preclinical and clinical pathway. In addition to this strategy, drug repositioning has also become an important complementary approach, which can be shorter, cheaper, and less risky. This review provides an overview of drug innovation in both human and veterinary medicine, with a focus on drug repositioning. The evolution of drug repositioning and the effectiveness of this approach are presented, including the growing role of data science and computational modeling methods in identifying drugs with po

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… Polypharmacology in our context means that the effectiveness of these drugs is due to their ability to influence the pathomechanism of the disease through affecting more than one, even several, pharmacologically relevant targets [ 46 , 47 ]. … In light of the above, polypharmacology can essentially be considered the first pharmacological background and model of disease- and target-based drug repositioning. …

Устранение неврологических расстройств путем борьбы с нейродегенеративными ассоциированными ферментами: естественные и синтетические молекулы.

Неврологические расстройства, включая нейродегенеративные и нейро-воспалительные заболевания, создают значительные проблемы в области здравоохранения и клинических проблем. Недавние исследования показали, что различные ферменты играют ключевую роль в наступлении и развитии этих расстройств. В этом обзоре изучается терапевтический потенциал адресации этих ферментов естественными и синтетическими молекулами. К таким заболеваниям, как болезнь Альцгеймера, болезнь Паркинсона и множественный склероз, причастны основные ферменты, включая ацетилхолинестеразу, оксидазу моноамина, бета-секретазу, тау к

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… Synergistic effects and polypharmacology are two well-established landmarks in the world of natural and nature-inspired substances. The entourage impact of various compounds on several biological targets and biochemical pathways frequently builds the foundation for the apparent therapeutic outcome. … Because these disorders are complex and caused by oxidative stress, inflammation, and protein aggregation, natural alkaloids with polypharmacological qualities can be used as nutraceuticals and in drug development. …

Repositioning of drugs for Parkinson's disease and pharmaceutical nanotechnology tools for their optimization.

Parkinson's disease (PD) significantly affects patients' quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science,

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… This is known as polypharmacology [ 36 ]. It could be beneficial when additional targets are relevant or part of some other pathology for which the drug was not indicated initially (Fig. 1 ). … Fig. 1 Drug repositioning and polypharmacology. …

Computational proteomics to enhance personalized treatment of COVID-19 and Long COVID.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to significant global health burden, including both acute infections and persistent post-acute sequelae, also known as Long COVID (LC) in survivors. While clinical management has reduced case-fatality rates, a substantial proportion of patients develop LC, a heterogeneous syndrome with long-term symptoms. This complex continuum requires therapeutic strategies for both the acute and chronic phases. Plasma proteomics has emerged as a powerful tool in precision medicin

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… Polypharmacology and multi-targeted agents Polypharmacology, targeting multiple pathways or proteins with a single drug, enhances the efficacy of COVID-19 treatments across diverse patient profiles. 2-deoxy-D-glucose (2-DG) demonstrates promise through glycolytic pathway effects, anti-inflammatory action … Methylene blue shows significant potential through polypharmacological action against SARS-CoV-2 as an inexpensive, widely available drug with minimal side effects [ 180 ]. …

Artificial Intelligence and Machine Learning Technology Driven Modern Drug Discovery and Development.

The discovery and advances of medicines may be considered as the ultimate relevant translational science effort that adds to human invulnerability and happiness. But advancing a fresh medication is a quite convoluted, costly, and protracted operation, normally costing USD ~2.6 billion and consuming a mean time span of 12 years. Methods to cut back expenditure and hasten new drug discovery have prompted an arduous and compelling brainstorming exercise in the pharmaceutical industry. The engagement of Artificial Intelligence (AI), including the deep-learning (DL) component in particular, has bee

Роль NLRP3 испарения в нейродегенеративных и метаболических заболеваниях и в соответствующих перспективных терапевтических вмешательствах.

Инфламасомы представляют собой внутриклеточные мультипротеиновые комплексы в цитоплазме, которые регулируют воспаление во врожденной иммунной системе в ответ на патогены и на прием самопроизводственных молекул. Последние достижения значительно улучшили наше понимание активации нуклеотидно-обязательного олигомеризации домена-подобный рецептору (NLR) семейный пирин, содержащий 3 (NLRP3) воспаление на молекулярном уровне. NLRP3 принадлежит подсемейству NLRP, которая активирует Caspase 1, что приводит к производству провоспалительных цитокинов (interleukin) 1β и интерлейкин 18) и пироптоз. Это вос

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… In this context, the polypharmacology of compounds seems promising for treating multifactorial diseases such as T2D and AD because it enables a single drug to inhibit multiple targets; this situation may increase its effectiveness against diseases. …

Exploiting artificial intelligence in precision oncology: an updated comprehensive review.

Precision oncology considers the genetic makeup of both the tumor and the cancer patient, medical history, clinical metadata, lifestyle and environmental factors. Thus, adoption of precision cancer medicine mandates sophisticated integrative analysis. Being a master in sorting and solving the puzzle pieces, artificial intelligence (AI)-powered frameworks emerged to fill the gap via executing multimodal analysis and generating meaningful outputs. Herein, we systematically discussed the opportunities and challenges of exploiting AI-assisted models in preclinical cancer research and in clinical o

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… AI-driven tools also have the potential to advance the field of polypharmacology (which refers to small molecules interacting with multiple targets simultaneously) through predicting their selectivity and off-target effects. …

GLP-1 Рецептор агонисты в неврологических расстройствах: от механизмов к клиническому переводу.

Глукагон-подобный peptide-1 агонисты рецепторов или GLP-1RAs, были использованы годами для обработки типа 2 диабет и ожирение. Совсем недавно стало ясно, что эти рецепторы широко распространяются по всей центральной нервной системе (СНС), что расширило возможность повторного использования этих лекарств для лечения неврологических расстройств. В этом обзоре мы анализируем улики по целому ряду неврологических условий, обсуждаем основные механизмы, которые, как предполагается, объясняют их нейрозащитные эффекты, и указываем на препятствия, которые еще предстоит устранить, прежде чем их можно буде

Predicting new drug indications for prostate cancer: The integration of an in silico proteochemometric network pharmacology platform with patient-derived primary prostate cells.

BackgroundDrug repurposing enables the discovery of potential cancer treatments using publically available data from over 4000 published Food and Drug Administration approved and experimental drugs. However, the ability to effectively evaluate the drug's efficacy remains a challenge. Impediments to broad applicability include inaccuracies in many of the computational drug-target algorithms and a lack of clinically relevant biologic modeling systems to validate the computational data for subsequent translation.MethodsWe have integrated our computational proteochemometric systems network pharmac

Каннабиноиды: терапевтические перспективы для борьбы с орофасиальной болью, оральное воспаление и систематическое обследование на предмет вылечения костей.

Каннабиноиды, в частности каннабидиол (КБР) и тетрагидроканнабинол (THC), все чаще изучаются на предмет их терапевтического применения в различных медицинских областях. Целью этого систематического обзора является изучение их роли в оральной хирургии с уделением особого внимания обезболиванию, воспалению и регенерации костей. Систематический обзор был проведен с использованием системы PRISMA для выявления соответствующих исследований из баз данных PubMed, Scopus и Web-сайта науки, опубликованных до ноября 2024. Обзор включал в себя клинические и предклинические исследования, посвященные изучен

Targeted phytotherapy: essential oils, multi-target cancer action & nanodelivery.

Biochemical components of essential oils (EOs) are an innovative but largely underexplored type of precision phytotherapy (PT) in oncology owing to their anticancer activity against many types of tumors. This article discusses the important multitargeted molecular mechanisms of EOs (apoptosis, cell cycle arrest, angiogenesis, metastasis, tumor microenvironment) and their role as antitumor agents. In particular, an effort has been made to emphasize on the most notable volatile EOs such as thymol, eugenol, limonene, β-caryophyllene, and their interaction with oncogenic signaling pathways (NF-κB,