RESUMEN
In this in silico study, we conducted an in-depth exploration of the potential of natural products and antihypertensive molecules that could serve as inhibitors targeting the key proteins of the SARS-CoV-2 virus: the main protease (Mpro) and the spike (S) protein. By utilizing Induced Fit Docking (IFD), we assessed the binding affinities of the molecules under study to these crucial viral components. To further comprehend the stability and molecular interactions of the "protein-ligand" complexes that derived from docking studies, we performed molecular dynamics (MD) simulations, shedding light on the molecular basis of potential drug candidates for COVID-19 treatment. Moreover, we employed Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations on all "protein-ligand" complexes, underscoring the robust binding capabilities of rosmarinic acid, curcumin, and quercetin against Mpro, and salvianolic acid b, rosmarinic acid, and quercetin toward the S protein. Furthermore, in order to expand our search for potent inhibitors, we conducted a structure similarity analysis, using the Enalos Suite, based on the molecules that indicated the most favored results in the in silico studies. The Enalos Suite generated 115 structurally similar compounds to salvianolic acid, rosmarinic acid, and quercetin. These compounds underwent IFD calculations, leading to the identification of two salvianolic acid analogues that exhibited strong binding to all the examined binding sites in both proteins, showcasing their potential as multi-target inhibitors. These findings introduce exciting possibilities for the development of novel therapeutic agents aiming to effectively disrupt the SARS-CoV-2 virus lifecycle.
Asunto(s)
Productos Biológicos , COVID-19 , Humanos , Antihipertensivos/farmacología , SARS-CoV-2 , Productos Biológicos/farmacología , Tratamiento Farmacológico de COVID-19 , Ligandos , Quercetina , Glicoproteína de la Espiga del Coronavirus , Simulación de Dinámica Molecular , Péptido Hidrolasas , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/farmacología , Antivirales/farmacología , Ácido RosmarínicoRESUMEN
The study of natural products as potential drug leads has gained tremendous research interest. Quercetin is one of those natural products. It belongs to the family of flavonoids and, more specifically, flavonols. This review summarizes the beneficial pharmaceutical effects of quercetin, such as its anti-cancer, anti-inflammatory, and antimicrobial properties, which are some of the quercetin effects described in this review. Nevertheless, quercetin shows poor bioavailability and low solubility. For this reason, its encapsulation in macromolecules increases its bioavailability and therefore pharmaceutical efficiency. In this review, a brief description of the different forms of encapsulation of quercetin are described, and new ones are proposed. The beneficial effects of applying new pharmaceutical forms of nanotechnology are outlined.
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Productos Biológicos , Quercetina , Quercetina/farmacología , Flavonoides , Flavonoles , Antiinflamatorios/farmacología , Preparaciones FarmacéuticasRESUMEN
The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled "Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology".
Asunto(s)
Antiprotozoarios/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Diseño de Fármacos , Leishmaniasis/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Tripanosomiasis Africana/tratamiento farmacológico , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/clasificación , Enfermedad de Chagas/parasitología , Enfermedad de Chagas/transmisión , Descubrimiento de Drogas , Humanos , Insectos Vectores/efectos de los fármacos , Insectos Vectores/parasitología , Leishmania/efectos de los fármacos , Leishmania/genética , Leishmania/crecimiento & desarrollo , Leishmania/metabolismo , Leishmaniasis/parasitología , Leishmaniasis/transmisión , Estadios del Ciclo de Vida/efectos de los fármacos , Estadios del Ciclo de Vida/genética , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Estructura Molecular , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Relación Estructura-Actividad , Trypanosoma brucei gambiense/efectos de los fármacos , Trypanosoma brucei gambiense/genética , Trypanosoma brucei gambiense/crecimiento & desarrollo , Trypanosoma brucei gambiense/metabolismo , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/genética , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/metabolismo , Tripanosomiasis Africana/parasitología , Tripanosomiasis Africana/transmisiónRESUMEN
The octapeptide hormone angiotensin II is one of the most studied peptides with the aim of designing and synthesizing non-peptide mimetics for oral administration. To achieve this, cyclizations at different positions within the peptide molecule has been a useful strategy to define the active conformation. These studies on angiotensin II led to the discovery of Sarmesin, a type II angiotensin II antagonist, and the breakthrough non-peptide mimetic Losartan, the first in a series of sartans marketed as a new generation of anti-hypertensive drugs in the 1990s. Angiotensin II receptor blockers (ARBS) and angiotensin I converting enzyme inhibitors (ACEI) were recently reported to protect hypertensive patients infected with SARS-CoV-2. The renin-angiotensin system (RAS) inhibitors reduce excess angiotensin II and increase antagonist heptapeptides alamandine and aspamandine which counterbalance angiotensin II and maintain homeostasis and vasodilation.
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Angiotensina II/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Humanos , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-ß-cyclodextrin (Que/HP-ß-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-ß-cyclodextrin (Que/Me-ß-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-ß-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-ß-CD more than with Me-ß-CD, possibly revealing the presence of more than one HP-ß-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-ß-CD and Que/HP-ß-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.
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2-Hidroxipropil-beta-Ciclodextrina/química , Encéfalo/efectos de los fármacos , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/métodos , Mucosa Nasal/efectos de los fármacos , Quercetina/administración & dosificación , Quercetina/química , beta-Ciclodextrinas/química , Administración Intranasal/métodos , Animales , Disponibilidad Biológica , Estabilidad de Medicamentos , Concentración de Iones de Hidrógeno , Quercetina/farmacocinética , Conejos , Solubilidad , Temperatura de TransiciónRESUMEN
A series of nineteen amino acid analogues of amantadine (Amt) and rimantadine (Rim) were synthesized and their antiviral activity was evaluated against influenza virus A (H3N2). Among these analogues, the conjugation of rimantadine with glycine illustrated high antiviral activity combined with low cytotoxicity. Moreover, this compound presented a profoundly high stability after in vitro incubation in human plasma for 24 h. Its thermal stability was established using differential and gravimetric thermal analysis. The crystal structure of glycyl-rimantadine revealed that it crystallizes in the orthorhombic Pbca space group. The structure-activity relationship for this class of compounds was established, with CoMFA (Comparative Molecular Field Analysis) 3D-Quantitative Structure Activity Relationships (3D-QSAR) studies predicting the activities of synthetic molecules. In addition, molecular docking studies were conducted, revealing the structural requirements for the activity of the synthetic molecules.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/farmacología , Antivirales/farmacología , Simulación por Computador , Orthomyxoviridae/efectos de los fármacos , Relación Estructura-Actividad Cuantitativa , Adamantano/síntesis química , Adamantano/química , Animales , Antivirales/síntesis química , Antivirales/química , Sitios de Unión , Muerte Celular/efectos de los fármacos , Cristalografía por Rayos X , Análisis Diferencial Térmico , Perros , Estabilidad de Medicamentos , Humanos , Enlace de Hidrógeno , Análisis de los Mínimos Cuadrados , Células de Riñón Canino Madin Darby , Conformación Molecular , Simulación del Acoplamiento Molecular , Dominios Proteicos , Rimantadina/sangre , Rimantadina/química , Temperatura , Proteínas de la Matriz Viral/químicaRESUMEN
Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1-7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE's protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE's ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.
RESUMEN
Introduction: Parkinson's Disease (PD) is a neurodegenerative central nervous system (CNS) disorder characterized by dopaminergic neuron degeneration with consequent reduction in striatal dopamine (DA) levels that leads to motor symptoms. Catechol-O-methyltransferase (COMT, E.C 2.1.1.6) inactivates dopamine and other substrates bearing catechol through the methylation of a hydroxyl group. COMT inhibition can block metabolism of catecholamines including DA. Since the increase in DA bioavailability is dependent on the inhibition of DA metabolism at the periphery, the development of COMT inhibitors as adjuvants to levodopa/aromatic amino acid decarboxylase (AADC) inhibitor treatment improves the clinical benefits of PD symptomatic treatment significantly.Areas covered: This review focuses on the contribution of computational studies to develop novel COMT inhibitors as therapeutics of Parkinson's disease with substantially improved efficacy.Expert opinion: The increasing use of in silico methods and the development of new chemoinformatic tools in combination with the knowledge gained from the development of different inhibitors studied both in silico, in vitro and in vivo, could help solve a number of issues related to the shortcomings of currently marketed treatments. They can also aid to open new avenues for centrally acting COMT inhibitors, and perhaps irreversible inhibitors, to be tested for PD and other neurological diseases.