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BACKGROUND: Propolis is a resinous compound that is obtained from honey bees. It consists of numerous chemical constituents that impart different therapeutic action. The heart is the core of the body and cardiovascular disease (CVD) is a burden for the human being. This article emphasizes how propolis is fruitful in the management of various CVDs. SCOPE AND APPROACH: This review focuses on how various constituents of the propolis (such as terpenes, flavonoids, phenolics, etc.) impart cardio protective actions. KEY FINDING AND CONCLUSION: With the support of various clinical trials and research outcomes, it was concluded that propolis owns niche cardio protective properties that can be a boon for various cardiac problems (both in preventive and therapeutic action) such as atherosclerosis, excessive angiogenesis, hypertension, and many more.
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Doenças Cardiovasculares , Própole , Animais , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Flavonoides/uso terapêutico , Flavonoides/química , Flavonoides/farmacologia , Própole/química , Própole/uso terapêuticoRESUMO
Diabetes is a widespread epidemic that includes a number of comorbid conditions that greatly increase the chance of acquiring other chronic illnesses. Every year, there are significantly more people with diabetes because of the rise in type-2 diabetes prevalence. The primary causes of illness and mortality worldwide are, among these, hyperglycemia and its comorbidities. There has been a lot of interest in the creation of peptide-based hydrogels as a potentially effective platform for the treatment of diabetes and its consequences. Here, we emphasize the use of self-assembled hydrogel formulations and their unique potential for the treatment/management of type-2 diabetes and its consequences. (i.e., wounds). Key aspects covered include the characteristics of self-assembled peptide hydrogels, methods for their preparation, and their pre-clinical and clinical applications in addressing metabolic disorders such as type-2 diabetes.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Humanos , Cicatrização , Hidrogéis/uso terapêutico , Peptídeos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológicoRESUMO
A significant portion of brain-tumor patients suffer from 'brain-tumor-related epilepsy (BTE)' which results in depression, anxiety and hampered quality of life. Conventional anti-epileptic drugs indicate negative interaction with other drugs augmenting the poor outcome of overall therapy. Levetiracetam (LVM) has evidenced effectiveness for BTE but its hydrophilicity restricts the passage into blood-brain barrier. The majority of lipid nanoparticles fails to load hydrophilic drug sufficiently. Therefore, lipid-drug conjugates (LDC) were synthesized using stearic acid via amide bond formation confirmed by FTIR and NMR. The nanoparticles of synthesized LDC were prepared by solvent injection method followed by functionalization with Apolipoprotein E3 (ApoE3@LDC-NP). The nanoparticles were characterized by DSC, XRD, particle size (131.6 ± 1.24 nm), zeta potential (-15.6 ± 0.09 mV), and for storage stability. In-vitro release study indicated initial burst release of 20 ± 0.63 % followed by sustained release up to 30 h (66 ± 1.40 %) for ApoE3@LDC-NP. The cell-line study on HEK293 indicated no significant cytotoxic effect and greater cell uptake through U87MG cell line. The pharmacokinetic and bio-distribution study indicated 2.5-fold greater brain-targeting of ApoE3@LDC-NP as compared to LVM solution. It proved safe in the haemolysis study and exhibited the absence of tissue necrosis. Thus, ApoE3@LDC-NP might be a promising approach for effective brain-targeting of LVM for improved clinical response in BTE.
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Neoplasias Encefálicas , Nanopartículas , Humanos , Apolipoproteína E3/metabolismo , Levetiracetam/farmacologia , Levetiracetam/metabolismo , Levetiracetam/uso terapêutico , Células HEK293 , Qualidade de Vida , Encéfalo/metabolismo , Lipossomos/metabolismo , Portadores de Fármacos/química , Nanopartículas/química , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Tamanho da Partícula , Sistemas de Liberação de MedicamentosRESUMO
Elevated circulating glucose level due to ß-cell dysfunction has been a key marker of Type-II diabetes. Glycogen synthase kinase-3 (GSK-3) has been recognized as an enzyme involved in the control of glycogen metabolism. Consequently, inhibitors of GSK-3 have been explored for anti-diabetic effects in vitro and in animal models. Further, the mechanisms governing the regulation of this enzyme have been elucidated by means of a combination of structural and cellular biological investigations. This review article examines the structural analysis of GSK-3 as well as molecular modeling reports from numerous researchers in the context of the design and development of GSK-3 inhibitors. This article centers on the signaling pathway of GSK-3 relevant to its potential as a target for diabetes and discusses advancements till date on different molecular modification approaches used by researchers in the development of novel GSK-3 inhibitors as potential therapeutics for the treatment of Type II diabetes.
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Diabetes Mellitus Tipo 2 , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Transdução de Sinais , Glicogênio Sintase Quinase 3 beta/metabolismoRESUMO
The COVID-19 pandemic has flared across every part of the globe and affected populations from different age groups differently. People aged from 40 to 80 years or older are at an increased risk of morbidity and mortality due to COVID-19. Therefore, there is an urgent requirement to develop therapeutics to decrease the risk of the disease in the aged population. Over the last few years, several prodrugs have demonstrated significant anti-SARS-CoV-2 effects in in vitro assays, animal models, and medical practice. Prodrugs are used to enhance drug delivery by improving pharmacokinetic parameters, decreasing toxicity, and attaining site specificity. This article discusses recently explored prodrugs such as remdesivir, molnupiravir, favipiravir, and 2-deoxy-D-glucose (2-DG) and their implications in the aged population, as well as investigating recent clinical trials.
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COVID-19 , Pró-Fármacos , Animais , Humanos , SARS-CoV-2 , Pandemias , Fosforilação , Antivirais/uso terapêuticoRESUMO
Cancer is one of the most prevalent diseases and affects a large proportion of the population worldwide. Conventional treatments in the management include chemotherapy, radiotherapy, and surgery. Although being well-accepted, they have many lacunas in the form of severe side effect resulting from lack of targeted delivery. Antibody biopolymer conjugates are a novel method which is an add-on to older methods of immunization. It is used in various diseases and disorders. It ensures the targeted delivery of molecules to increase its efficacy and reduce unwanted effects of the molecule/drug to normal cells. It shows miraculous results in the treatment and management of several cancers even in advanced stages. Herein, we present the chemistry between biopolymer and antibody, their effects on cancer as well as the basic differences between antibody-drug conjugates and antibody-biopolymer conjugates.
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Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Anticorpos/uso terapêutico , Neoplasias/tratamento farmacológico , Oncologia , Imunoconjugados/uso terapêutico , Biopolímeros/uso terapêutico , Antineoplásicos/químicaRESUMO
Propolis is a mass of chemically diverse phytoconstituents with gummy textures that are naturally produced by honeybees upon collection of plant resins for utilization in various life processes in beehives. Since ancient times, propolis has been a unique traditional remedy globally utilized for several purposes, and it has secured value in pharmaceutical and nutraceutical areas in recent years. The chemical composition of propolis comprises diverse constituents and deviations in the precise composition of the honeybee species, plant source used for propolis production by bees, climate conditions and harvesting season. Over 300 molecular structures have been discovered from propolis, and important classes include phenolic acids, flavonoids, terpenoids, benzofurans, benzopyrene and chalcones. Propolis has also been reported to have diverse pharmacological activities, such as antidiabetic, anti-inflammatory, antioxidant, anticancer, immunomodulatory, antibacterial, antiviral, antifungal, and anticaries. As chronic diseases have risen as a global health threat, abundant research has been conducted to track propolis and its constituents as alternative therapies for chronic diseases. Several clinical trials have also revealed the potency of propolis and its constituents for preventing and curing some chronic diseases. This review explores the beneficial effect of propolis and its active constituents with credible mechanisms and computational studies on chronic diseases.
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The nucleoside analog ß-D-N4-hydroxycytidine is the active metabolite of the prodrug molnupiravir and is accepted as an efficient drug against COVID-19. Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) enzyme, which is responsible for replicating the viral genome during the replication process of certain types of viruses. It works by disrupting the normal function of the RdRp enzyme, causing it to make mistakes during the replication of the viral genome. These mistakes can prevent the viral RNA from being transcribed, converted into a complementary DNA template, translated, or converted into a functional protein. By disrupting these crucial steps in the viral replication process, molnupiravir can effectively inhibit the replication of the virus and reduce its ability to cause disease. This review article sheds light on the impact of molnupiravir and its metabolite on SARS-CoV-2 variants of concern, such as delta, omicron, and hybrid/recombinant variants. The detailed mechanism and molecular interactions using molecular docking and dynamics have also been covered. The safety and tolerability of molnupiravir in patients with comorbidities have also been emphasized.
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The SARS-CoV-2 virus has been identified as a causative agent for COVID-19 pandemic. About more than 6.3 million fatalities have been attributed to COVID-19 worldwide to date. Finding a viable cure for the illness is urgently needed in light of the present pandemic. The prominence of main protease in the life cycle of virus shapes the main protease as a viable target for design and development of antiviral agents to combat COVID-19. The current study presents the fragment linking strategy to design the novel Mpro inhibitors for COVID-19. A total of 293,451 fragments from diversified libraries have been screened for their binding affinity towards Mpro enzyme. The best 1600 fragment hits were subjected to fragment joining to achieve 100 new molecules using Schrödinger software. The resulting molecules were further screened for their Mpro binding affinity, ADMET, and drug-likeness features. The best 13 molecules were selected, and the first 6 compounds were investigated for their ligand-receptor complex stability through a molecular dynamics study using GROMACS software. The resulting molecules have the potential to be further evaluated for COVID-19 drug discovery.
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The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a 'twincretin', is a 'first-in-class' and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the 'twincretin' era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.
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Diabetes Mellitus Tipo 2 , Polipeptídeo Inibidor Gástrico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismoRESUMO
With the aim to combat a multi-faceted neurodegenerative Alzheimer's disease (AD), a series of carbazole-based semicarbazide and hydrazide derivatives were designed, synthesized and assessed for their cholinesterase (ChE) inhibitory, antioxidant and biometal chelating activity. Among them, (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(pyridin-2-yl)hydrazinecarbothioamide (62) and (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(5-chloropyridin-2-yl)hydrazinecarbothioamide (63) emerged as the premier candidates with good ChE inhibitory activities (IC50 values of 1.37 µM and 1.18 µM for hAChE, IC50 values of 2.69 µM and 3.31 µM for EqBuChE, respectively). All the test compounds displayed excellent antioxidant activity (reduction percentage of DPPH values for compounds (62) and (63) were 85.67% and 84.49%, respectively at 100 µM concentration). Compounds (62) and (63) conferred specific copper ion chelating property in metal chelation study. Molecular docking studies of compounds (62) and (63) indicate strong interactions within the active sites of both the ChE enzymes. Besides that, these compounds also exhibited significant in silico drug-like pharmacokinetic properties. Thus, taken together, they can serve as a starting point in the designing of multifunctional ligands in pursuit of potential anti-AD agents that might further prevent the progression of ADs.Communicated by Ramaswamy H. Sarma.
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Doença de Alzheimer , Semicarbazonas , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Acetilcolinesterase/química , Semicarbazonas/farmacologia , Hidrazonas , Simulação de Acoplamento Molecular , Carbazóis/farmacologia , Carbazóis/química , Quelantes/farmacologia , Quelantes/química , Antioxidantes/farmacologia , Antioxidantes/química , Doença de Alzheimer/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19.
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Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Programas de Rastreamento/métodos , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
The inadequate clinical efficacy of the present anti-Alzheimer's disease (AD) drugs and their low impact on the progression of Alzheimer's disease in patients have revised the research focus from single targets to multitarget-directed ligands. A novel series of substituted triazinoindole derivatives were obtained by introducing various substituents on the indole ring for the development of multitarget-directed ligands as anti-AD agents. The experimental data indicated that some of these compounds exhibited significant anti-AD properties. Among them, 8-(piperidin-1-yl)-N-(6-(pyrrolidin-1-yl)hexyl)-5H-[1,2,4]triazino[5,6-b]indol-3-amine (60), the most potent cholinesterase inhibitor (AChE, IC50 value of 0.32 µM; BuChE, IC50 value of 0.21 µM), was also found to possess significant self-mediated Aß1-42 aggregation inhibitory activity (54% at 25 µM concentration). Additionally, compound 60 showed strong antioxidant activity. In the PAMPA assay, compound 60 exhibited blood-brain barrier penetrating ability. An acute toxicity study in rats demonstrated no sign of toxicity at doses up to 2000 mg/kg. Furthermore, compound 60 significantly restored the cognitive deficits in the scopolamine-induced mice model and Aß1-42-induced rat model. In the in silico ADMET prediction studies, the compound satisfied all the parameters of CNS acting drugs. These results highlighted the potential of compound 60 to be a promising multitarget-directed ligand for the development of potential anti-AD drugs.
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Doença de Alzheimer , Preparações Farmacêuticas , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Humanos , Ligantes , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aß aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 µM) and BuChE (IC50 value of 1.29 µM), and significant inhibition of self-mediated Aß1-42 aggregation (51.29% at 25 µM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aß1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.
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Doença de Alzheimer/tratamento farmacológico , Estilbenos/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Historically, plants have been sought after as bio-factories for the production of diverse chemical compounds that offer a multitude of possibilities to cure diseases. To combat the current pandemic coronavirus disease 2019 (COVID-19), plant-based natural compounds are explored for their potential to inhibit the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The present study is aimed at the investigation of antiviral action of several groups of phytoconstituents against SARS-CoV-2 using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to ACE2 (PDB code: 6M0J) of SARS-CoV-2. For binding affinity evaluation, the docking scores were calculated using the Extra Precision (XP) protocol of the Glide docking module of Maestro. CovDock was also used to investigate covalent docking. The OPLS3e force field was used in simulations. The docking score was calculated by preferring the conformation of the ligand that has the lowest binding free energy (best pose). The results are indicative of better potential of solanine, acetoside, and rutin, as Mpro and spike glycoprotein RBD dual inhibitors. Acetoside and curcumin were found to inhibit Mpro covalently. Curcumin also possessed all the physicochemical and pharmacokinetic parameters in the range. Thus, phytochemicals like solanine, acetoside, rutin, and curcumin hold potential to be developed as treatment options against COVID-19.