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BACKGROUND: Cancer involves uncontrolled cell growth due to genetic mutations. Tumors can form when CDK6, a gene essential for controlling cell growth, isn't working correctly. Researchers are investigating drugs that inhibit CDK6; some of them appear promising. Nevertheless, CDK6 is advantageous and harmful to cancer because it controls other cellular processes. By inhibiting CDK6 and CDK4, CDK4/6 inhibitors offer a novel therapeutic strategy that stops cell proliferation. The study investigates the function of CDK6 in cancer, the difficulties in targeting CDK6, and possible remedies. OBJECTIVE: Scientists have developed drugs designed to block CDK6 and prevent it from altering other proteins. These drugs, also known as CDK6 inhibitors, help treat cancer. Finding the best drugs for CDK6 is still tricky, though. The drugs' selectivity, potency, and cost are some difficulties. These factors depend on CDK6's structure and interactions with other proteins. The structure of CDK6 and how it influences its function and regulation are explained in this review. It also describes CDK6's function in cancer and its interaction with other molecules and proteins, which is crucial for cell division. Moreover, this review describes how CDK6 interacts with the drugs that block it and what the current and future treatments that target CDK6 are. CONCLUSION: This review presents the structure, current research, and overview of CDK6. It also reviews the role of CDK6 in cancer, function, and regulation. Additionally, it explores its role in cancer signaling networks and its interaction with CDK6 inhibitors. Lastly, it discusses the current status and prospects of therapies targeting CDK6.
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Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (Ka = 7.6 × 105M-1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC50 value of 3.10 µM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6.
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Quinasa 6 Dependiente de la Ciclina , Neoplasias , Humanos , Rutina/farmacología , Simulación del Acoplamiento Molecular , Fosforilación , Procesamiento Proteico-PostraduccionalRESUMEN
A quarter of a century ago, designer peptide drugs finally broke through the glass ceiling. Despite the resistance by big pharma, biotechnology companies managed to develop injectable peptide-based drugs, first against orphan or other small volume diseases, and later for conditions affecting large patient populations such as type 2 diabetes. Even their lack of gastrointestinal absorption could be utilized to enable successful oral dosing against chronic constipation. The preference of peptide therapeutics over small molecule competitors against identical medical conditions can be achieved by careful target selection, intrachain and terminal amino acid modifications, appropriate conjugation to stability enhancers and chemical space expansion, innovative delivery and administration techniques and patient-focused marketing strategies. Unfortunately, however, pharmacoeconomical considerations, including the strength of big pharma to develop competing small molecule drugs, have somewhat limited the success of otherwise smart peptide-based therapeutics. Yet, with increasing improvement in peptide drug modification and formulation, these are continuing to gain significant, and growing, acceptance as desirable alternatives to small molecule compounds.
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N-heterocyclic scaffolds represent a privileged architecture in the process of drug design and development. It has widespread occurrence in synthetic and natural products, either those that are established or progressing as potent drug candidates. Additionally, numerous novel N-heterocyclic analogues with remarkable physiological significance and extended pharmaceutical applications are escalating progressively. Hence, the classical synthetic protocols need to be improvised according to modern requirements for efficient and eco-friendly approaches. Numerous methodologies and technologies emerged to address the green and sustainable production of various pharmaceutically and medicinally important N-heterocyclic compounds in last few years. In this context, the current review unveils greener alternatives for direct access to categorically differentiated N-heterocyclic derivatives and its application in the establishment of biologically active potent molecules for drug design. The green and sustainable methods accentuated in this review includes microwave-assisted reactions, solvent-free approaches, heterogeneous catalysis, ultrasound reactions, and biocatalysis.
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During the last twenty years, organic fluorination chemistry established itself as an important tool to get a biologically active compound. This belief can be supported by the fact that every year, we are getting fluorinated drugs in the market in extremely significant numbers. Last year, also ten fluorinated drugs have been approved by FDA and during the COVID-19 pandemic, fluorinated drugs played a very crucial role to control the disease and saved many lives. In this review, we surveyed all ten fluorinated drugs approved by FDA in 2021 and all fluorinated drugs which were directly-indirectly used during the COVID-19 period, and emphasis has been given particularly to their synthesis, medicinal chemistry, and development process. Out of ten approved drugs, one drug pylarify, a radioactive diagnostic agent for cancer was approved for use in positron emission tomography imaging. Also, very briefly outlined the significance of fluorinated drugs through their physical, and chemical properties and their effect on drug development.
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The strategic fluorination of oxidatively vulnerable sites in bioactive compounds is a relatively recent, widely used approach allowing us to modulate the stability, bio-absorption, and overall efficiency of pharmaceutical drugs. On the other hand, natural and tailor-made amino acids are traditionally used as basic scaffolds for the development of bioactive molecules. The main goal of this review article is to emphasize these general trends featured in recently approved pharmaceutical drugs.
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Antifibrinolíticos , Flúor , Flúor/química , Aminoácidos/química , Halogenación , Preparaciones FarmacéuticasRESUMEN
Monkeypox virus (MPXV) outbreak in non-endemic countries is a worldwide public health emergency. An enveloped double-stranded DNA virus belongs to the genus Orth poxvirus. A viral zoonotic infection known as monkeypox has been a serious risk to public health, especially in Africa. However, it has recently spread to other continents, so it might soon become a worldwide problem. There is an increased risk of transmission of the virus because there is a lack of effective treatment that cures the disease. To stop the multi-country outbreak from spreading, it is important to discover effective medications urgently. The objective of the current study is to swiftly find new treatments for the monkeypox virus using advanced computational approaches. By investigating five potential MPXV targets (DNA ligase, Palmytilated Extracellular Enveloped Virus (EEV) membrane protein, Scaffold protein D13, Thymidylate Kinase, and Viral core cysteine proteinase), this research was carried out using cutting-edge computational techniques against human monkeypox virus infection. Here we present the accurate 3D structures and their binding cavities of the selected targets with higher confidence using AlphaFold 2 and SiteMap analysis. Molecular docking and MD simulation analysis revealed the top five potential lead compounds with higher binding affinity and stability toward selected targets. Binding free energy calculations and other essential dynamics analysis supports the finding. The selected lead compounds utilizing virtual screening and drug repurposing approach reported in this study are beneficial for medical scientists and experimental biologists in drug development for the treatment of human MPXV.Communicated by Ramaswamy H. Sarma.
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Mpox , Humanos , Mpox/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Proteínas de la Membrana , Simulación por Computador , ADN LigasasRESUMEN
AlphaFold2 is a promising new tool for researchers to predict protein structures and generate high-quality models, with low backbone and global root-mean-square deviation (RMSD) when compared with experimental structures. However, it is unclear if the structures predicted by AlphaFold2 will be valuable targets of docking. To address this question, we redocked ligands in the PDBbind datasets against the experimental co-crystallized receptor structures and against the AlphaFold2 structures using AutoDock-GPU. We find that the quality measure provided during structure prediction is not a good predictor of docking performance, despite accurately reflecting the quality of the alpha carbon alignment with experimental structures. Removing low-confidence regions of the predicted structure and making side chains flexible improves the docking outcomes. Overall, despite high-quality prediction of backbone conformation, fine structural details limit the naive application of AlphaFold2 models as docking targets.
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Diseño de Fármacos , Proteínas , Proteínas/química , Ligandos , Simulación del Acoplamiento Molecular , Conformación Proteica , Unión ProteicaRESUMEN
The integration of artificial intelligence in precision medicine has revolutionized healthcare delivery. Precision medicine identifies the phenotype of particular patients with less-common responses to treatment. Recent studies have demonstrated that translational research exploring the convergence between artificial intelligence and precision medicine will help solve the most difficult challenges facing precision medicine. Here, we discuss different aspects of artificial intelligence in precision medicine that improve healthcare delivery. First, we discuss how artificial intelligence changes the landscape of precision medicine and the evolution of artificial intelligence in precision medicine. Second, we highlight the synergies between artificial intelligence and precision medicine and promises of artificial intelligence and precision medicine in healthcare delivery. Third, we briefly explain the promise of big data analytics and the integration of nanomaterials in precision medicine. Last, we highlight the challenges and opportunities of artificial intelligence in precision medicine.
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Inteligencia Artificial , Medicina de Precisión , Macrodatos , Análisis de Datos , Aprendizaje AutomáticoRESUMEN
Cyclin-dependent kinase 6 (EC 2.7.11.22) play significant roles in numerous biological processes and triggers cell cycle events. CDK6 controlled the transcriptional regulation. A dysregulated function of CDK6 is linked with the development of progression of multiple tumor types. Thus, it is considered as an effective drug target for cancer therapy. Based on the direct roles of CDK4/6 in tumor development, numerous inhibitors developed as promising anti-cancer agents. CDK4/6 inhibitors regulate the G1 to S transition by preventing Rb phosphorylation and E2F liberation, showing potent anti-cancer activity in several tumors, including HR+/HER2- breast cancer. CDK4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib, control cell cycle, provoke cell senescence, and induces tumor cell disturbance in pre-clinical studies. Here, we discuss the roles of CDK6 in cancer along with the present status of CDK4/6 inhibitors in cancer therapy. We further discussed, how structural features of CDK4/6 could be implicated in the design and development of potential anti-cancer agents. In addition, the therapeutic potential and limitations of available CDK4/6 inhibitors are described in detail. Recent pre-clinical and clinical information for CDK4/6 inhibitors are highlighted. In addition, combination of CDK4/6 inhibitors with other drugs for the therapeutic management of cancer are discussed.
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Antineoplásicos , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Neoplasias , Inhibidores de Proteínas Quinasas , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ciclo Celular , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Humanos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Cyclin-dependent kinases (CDKs) play significant roles in numerous physiological, and are considered an attractive drug target for cancer, neurodegenerative, and inflammatory diseases. In the present study, we have aimed to investigate the binding affinity and inhibitory potential of selonsertib toward CDK6. Using the drug repurposing approach, we performed molecular docking of selonsertib with CDK6 and observed a significant binding affinity. To ascertain, we further performed essential dynamics analysis and free energy calculation, which suggested the formation of a stable selonsertib-CDK6 complex. The in-silico findings were further experimentally validated. The recombinant CDK6 was expressed, purified, and treated with selonsertib. The binding affinity of selonsertib to CDK6 was estimated by fluorescence binding studies and enzyme inhibition assay. The results indicated an appreciable binding of selonsertib against CDK6, which subsequently inhibits its activity with a commendable IC50 value (9.8 µM). We concluded that targeting CDK6 by selonsertib can be an efficient therapeutic approach to cancer and other CDK6-related diseases. These observations provide a promising opportunity to utilize selonsertib to address CDK6-related human pathologies.
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Isatin (1H indole 2, 3-dione) is a heterocyclic, endogenous lead molecule recognized in humans and different plants. The isatin nucleus and its derivatives are owed the attention of researchers due to their diverse pharmacological activities such as anticancer, anti-TB, antifungal, antimicrobial, antioxidant, anti-inflammatory, anticonvulsant, anti-HIV, and so on. Many research chemists take advantage of the gentle structure of isatins, such as NH at position 1 and carbonyl functions at positions 2 and 3, for designing biologically active analogues via different approaches. Literature surveys based on reported preclinical, clinical, and patented details confirm the multitarget profile of isatin analogues and thus their importance in the field of medicinal chemistry as a potent chemotherapeutic agent. This review represents the recent development of isatin analogues possessing potential pharmacological action in the years 2016-2020. The structure-activity relationship is also discussed to provide a pharmacophoric pattern that may contribute in the future to the design and synthesis of potent and less toxic therapeutics.
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Potent, cell-permeable, and subtype-selective sialyltransferase inhibitors represent an attractive family of substances that can potentially be used for the clinical treatment of cancer metastasis. These substances operate by specifically inhibiting sialyltransferase-mediated hypersialylation of cell surface glycoproteins or glycolipids, which then blocks the sialic acid recognition pathway and leads to deterioration of cell motility and invasion. A vast amount of evidence for the in vitro and in vivo effects of sialyltransferase inhibition or knockdown on tumor progression and tumor cell metastasis or colonization has been accumulated over the past decades. In this regard, this review comprehensively discusses the results of studies that have led to the recent discovery and development of sialyltransferase inhibitors, their potential biomedical applications in the treatment of cancer metastasis, and their current limitations and future opportunities.
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Sialiltransferasas , Animales , Humanos , NeoplasiasRESUMEN
The role of amino acids (AAs) in modern health industry is well-appreciated. Residues of individual AAs, or their chemical modifications, such as diamines and amino alcohols, are frequently found in the structures of modern pharmaceuticals. The goal of this review article, is to emphasize that, currently, tailor-made AAs serve as key structural features in many most successful pharmaceuticals, so-called blockbuster drugs. In the present article, we profile 14 small-molecule drugs, underscoring the breadth of structural variety of AAs applications in numerous therapeutic areas. For each compound, we provide spectrum of biological activity, medicinal chemistry discovery, and synthetic approaches.
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Aminoácidos/farmacología , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Aminoácidos/química , Química Farmacéutica , Humanos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.
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Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer's disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.
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A bottleneck that is hindering therapeutics innovation in cancers is the current lack of integration of what we have learned in tumor biology as well as the tumor microenvironment (TME). This is because tumors are complex tissues composed of cancer cells, stromal cells, and the extracellular matrix (ECM). Although genetic alterations might cause the initial uncontrolled growth, resistance to apoptosis in cancer cells and stromal cells play additional key roles within the TME and thus influence tumor initiation, progression, therapy resistance, and metastasis. Therapies targeting cancer cells are usually insufficient when the stromal component of the TME causes therapy resistance. For innovation in cancer treatment and to take a full snapshot of cancer biology, anticancer drug design must, therefore, target both cancer cells and the stromal component. This expert review critically examines the TME components such as cancer-associated fibroblasts and ECM that can be reprogrammed to create a tumor-suppressive environment, thereby aiding in tumor treatment. Better cancer experimental models that mimic the TME such as tumor spheroids, microfluidics, three dimensional (3D) bioprinted models, and organoids will allow deeper investigations of the TME complexity and can lead to the translation of basic tumor biology to effective cancer treatments. Ultimately, innovative cancer treatments and, by extension, improvement in cancer patients' outcomes will emerge from combinatorial drug development strategies targeting both cancer cells and stromal components of the TME. Combinatorial treatment strategies can take the form of chemotherapy and radiotherapy (targeting tumor cells and stromal components) and immunotherapy that is able to regulate immune responses against tumor cells. This expert review thus addresses a previously neglected knowledge gap in cancer drug design and development by broadening the focus in cancer biology to TME so as to empower disruptive health care innovations in the oncology clinic.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/inmunología , Inmunoterapia/métodos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Biomarcadores de Tumor/inmunología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/patología , Progresión de la Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/inmunología , Matriz Extracelular/patología , Humanos , Metástasis Linfática , Neoplasias/inmunología , Neoplasias/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Organoides/efectos de los fármacos , Organoides/inmunología , Organoides/patología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/inmunología , Esferoides Celulares/patología , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunología , Células del Estroma/patología , Microambiente Tumoral/inmunologíaRESUMEN
γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled receptors. Each class of GABA receptor has distinct pharmacology and physiology. GABAA receptors are heteropentameric transmembrane protein complexes made up of α1-6, ß1-3, γ1-3, δ, ε, θ, π subunits, giving rise to numerous allosteric binding sites and have thus attracted much attention targets for the treatment of conditions such as epilepsy, anxiety and sleep disorders. The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.
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Moduladores del GABA/farmacología , Receptores de GABA/metabolismo , Sitio Alostérico/efectos de los fármacos , Carbolinas/química , Carbolinas/farmacología , Etomidato/química , Etomidato/farmacología , Moduladores del GABA/química , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Ligandos , Estructura Molecular , Propofol/química , Propofol/farmacología , Quinolinas/química , Quinolinas/farmacología , Esteroides/química , Esteroides/farmacologíaRESUMEN
Several years after its isolation from melanoma cells, an increasing body of experimental evidence has established the involvement of Autotaxin (ATX) in the pathogenesis of several diseases. ATX, an extracellular enzyme responsible for the hydrolysis of lysophosphatidylcholine (LPC) into the bioactive lipid lysophosphatidic acid (LPA), is overexpressed in a variety of human metastatic cancers and is strongly implicated in chronic inflammation and liver toxicity, fibrotic diseases, and thrombosis. Accordingly, the ATX-LPA signaling pathway is considered a tractable target for therapeutic intervention substantiated by the multitude of research campaigns that have been successful in identifying ATX inhibitors by both academia and industry. Furthermore, from a therapeutic standpoint, the entry and the so far promising results of the first ATX inhibitor in advanced clinical trials against idiopathic pulmonary fibrosis (IPF) lends support to the viability of this approach, bringing it to the forefront of drug discovery efforts. The present review article aims to provide a comprehensive overview of the most important series of ATX inhibitors developed so far. Special weight is lent to the design, structure activity relationship and mode of binding studies carried out, leading to the identification of advanced leads. The most significant in vitro and in vivo pharmacological results of these advanced leads are also summarized. Lastly, the development of the first ATX inhibitor entered in clinical trials accompanied by its phase 1 and 2a clinical trial data is disclosed.
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Ensayos Clínicos como Asunto , Desarrollo de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Investigación Biomédica Traslacional , Animales , Humanos , Hidrolasas Diéster Fosfóricas/químicaRESUMEN
The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compound" has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery.