RESUMEN
Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.
Asunto(s)
Neuroblastoma , Farmacóforo , Animales , Humanos , Antidepresivos/farmacología , Inhibidores de la Monoaminooxidasa/química , Monoaminooxidasa/metabolismo , Relación Estructura-ActividadRESUMEN
Despite the various research efforts towards the drug discovery program for Zika virus treatment, no antiviral drugs or vaccines have yet been discovered. The spread of the mosquito vector and ZIKV infection exposure is expected to accelerate globally due to continuing global travel. The NS3-Hel is a non-structural protein part and involved in different functions such as polyprotein processing, genome replication, etc. It makes an NS3-Hel protein an attractive target for designing novel drugs for ZIKV treatment. This investigation identifies the novel, potent ZIKV inhibitors by virtual screening and elucidates the binding pattern using molecular docking and molecular dynamics simulation studies. The molecular dynamics simulation results indicate dynamic stability between protein and ligand complexes, and the structures keep significantly unchanged at the binding site during the simulation period. All inhibitors found within the acceptable range having drug-likeness properties. The synthetic feasibility score suggests that all screened inhibitors can be easily synthesizable. Therefore, possible inhibitors obtained from this study can be considered a potential inhibitor for NS3 Hel, and further, it could be provided as a lead for drug development.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Humanos , Virus Zika/química , Virus Zika/metabolismo , Infección por el Virus Zika/tratamiento farmacológico , Infección por el Virus Zika/metabolismo , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Proteínas no Estructurales Virales , ARN Helicasas/química , ARN Helicasas/genética , ARN Helicasas/metabolismo , Antivirales/química , Inhibidores de Proteasas/farmacologíaRESUMEN
There are several potential side and adverse effects are found to be associated with the anti-inflammatory drugs in clinical practice. The long-term use of these clinical agents highly unsafe. It encouraged the development of novel heterocyclic compounds with potential anti-inflammatory activity and low to no toxicity. In present investigation, a total of 12 indole functionalized pyrazole and oxadiazole derivatives were designed, synthesized and evaluated for the in-vivo anti-inflammatory and analgesic potential. These compounds displayed comparable anti-inflammatory and analgesic potential to the reference drugs. Finally, molecular docking analysis was performed considering different anti-inflammatory targets to determine the mechanistic target of the designed molecules. Detailed analysis suggested that the molecules inhibit COX-2, preferably over other anti-inflammatory targets. The results suggested that two compounds (15c and 15f) were found promising candidates for the development of novel anti-inflammatory agents.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Indoles/farmacología , Oxadiazoles/farmacología , Pirazoles/farmacología , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Carragenina , Bovinos , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Humanos , Indoles/química , Masculino , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Picratos/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Xanthine oxidase (XO) has been primarily targeted for the development of anti-hyperuriciemic /anti-gout agents as it catalyzes the conversion of xanthine and hypoxanthine into uric acid. XO overexpression in various cancer is very well correlated due to reactive oxygen species (ROS) production and metabolic activation of carcinogenic substances during the catalysis. Herein, we report the design and synthesis of a series of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehyde derivatives (2a-2x) as xanthine oxidase inhibitors (XOIs). A docking model was developed for the prediction of XO inhibitory activity of our novel compounds. Furthermore, our compounds anticancer activity results in low XO expression and XO-harboring cancer cells both in 2D and 3D-culture models are presented and discussed. Among the array of synthesized compounds, 2b and 2m emerged as potent XO inhibitors having IC50 values of 9.32 ± 0.45 µM and 10.03 ± 0.43 µM, respectively. Both compounds induced apoptosis, halted the cell cycle progression at the G1 phase, elevated ROS levels, altered mitochondrial membrane potential, and inhibited antioxidant enzymes. The levels of miRNA and expression of redox sensors in cells were also altered due to increase oxidative stress induced by our compounds. Compounds 2b and 2m hold a great promise for further development of XOIs for the treatment of XO-harboring tumors.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Pirazoles/química , Xantina Oxidasa/metabolismo , Aldehídos/química , Apoptosis/efectos de los fármacos , Sitios de Unión , Dominio Catalítico , Línea Celular Tumoral , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Cinética , Potencial de la Membrana Mitocondrial , MicroARNs/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo/efectos de los fármacos , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/metabolismo , Pirazoles/metabolismo , Pirazoles/farmacología , Relación Estructura-Actividad Cuantitativa , Especies Reactivas de Oxígeno/metabolismo , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
SARS-CoV-2 (COVID-19) epidemic has created an unprecedented medical and economic crisis all over the world. SARS-CoV-2 is found to have more contagious character as compared to MERS-CoV and is spreading in a very fast manner all around the globe. It has affected over 31 million people all over the world till date. This virus shares around 80% of genome similarity with SARS-CoV. In this perspective, we have explored three major targets namely; SARS-CoV-2 spike (S) protein, RNA dependent RNA polymerase, and 3CL or Mpro Protease for the inhibition of SARS-CoV-2. These targets have attracted attention of the medicinal chemists working on computer-aided drug design in developing new small molecules that might inhibit these targets for combating COVID-19 disease. Moreover, we have compared the similarity of these target proteins with earlier reported coronavirus (SARS-CoV). We have observed that both the coronaviruses share around 80% similarity in their amino acid sequence. The key amino acid interactions which can play a crucial role in designing new small molecule inhibitors against COVID-19 have been reported in this perspective. Authors believe that this study will help the medicinal chemists to understand the key amino acids essential for interactions at the active site of target proteins in SARS-CoV-2, based on their similarity with earlier reported viruses. In this review, we have also described the lead molecules under various clinical trials for their efficacy against COVID-19.
Asunto(s)
Antivirales/metabolismo , SARS-CoV-2/química , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/química , Proteínas no Estructurales Virales/metabolismo , Proteínas Estructurales Virales/metabolismo , Secuencia de Aminoácidos , Animales , Antivirales/uso terapéutico , Sitios de Unión , COVID-19/epidemiología , COVID-19/virología , Reposicionamiento de Medicamentos , Humanos , Unión Proteica , SARS-CoV-2/efectos de los fármacos , Proteínas no Estructurales Virales/química , Proteínas Estructurales Virales/química , Tratamiento Farmacológico de COVID-19RESUMEN
In the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) 'interfacial' inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.
Asunto(s)
ADN-Topoisomerasas de Tipo I/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Histona Desacetilasas/efectos de los fármacos , Quinazolinas/uso terapéutico , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Quinazolinas/químicaRESUMEN
A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC50â¯<â¯2.5⯵M) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Paladio/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/química , Quinazolinas/química , Apoptosis/efectos de los fármacos , Sitios de Unión , Catálisis , Dominio Catalítico , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/química , Clorhidrato de Erlotinib/metabolismo , Clorhidrato de Erlotinib/farmacología , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/metabolismo , Pirazoles/farmacología , Quinazolinas/metabolismo , Quinazolinas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-ActividadRESUMEN
Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases' binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X-ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.
Asunto(s)
Aldehído Oxidasa/química , Hígado/efectos de los fármacos , Molibdeno/química , Xantina Deshidrogenasa/química , Animales , Técnicas Biosensibles , Dominio Catalítico , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Oxidación-Reducción , Estrés Oxidativo , Conformación ProteicaRESUMEN
PURPOSE: Cyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab. METHODS: A total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5 × 10-8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome. RESULTS: Two gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17 bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group. CONCLUSION: CYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.
Asunto(s)
Aldehído Deshidrogenasa/genética , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Citocromo P-450 CYP2C19/genética , Doxorrubicina/administración & dosificación , Adulto , Anciano , Familia de Aldehído Deshidrogenasa 1 , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/farmacocinética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Quimioterapia Adyuvante/métodos , Ciclofosfamida/farmacocinética , Doxorrubicina/farmacocinética , Femenino , Genotipo , Humanos , India , Análisis por Micromatrices/métodos , Persona de Mediana Edad , Análisis de Regresión , Retinal-Deshidrogenasa , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The design and synthesis of dihydropyrazolo[1,5-c]quinazolines (1a-h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.
Asunto(s)
Antineoplásicos/farmacología , Glioma/tratamiento farmacológico , Quinazolinas/farmacología , Inhibidores de Topoisomerasa II/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Glioma/enzimología , Humanos , Modelos Moleculares , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
Drugs carrying an unsaturated CâC center (such as furans) form reactive epoxide metabolites and cause irreversible mechanism-based inactivation (MBI) of cytochrome P450 (CYP450) activity, through covalent modification of amino acid residues. Though this reaction is confirmed to take place in the active site of CYPs, the details of the reactions of furan (epoxidation and epoxide ring opening), the conditions under which MBI may occur, the residues involved, the importance of the heme center, etc. have yet to be explored. A density functional theory (DFT) study was carried out (i) to elucidate the reaction pathways for the generation of furan epoxide metabolite from furan ring by the model oxidant Cpd I (iron(IV)-oxo heme-porphine radical cation, to mimic the catalytic domain of CYPs) and (ii) to explore different reactions of the furan epoxide metabolite. The energy profiles of the competitive pathways and the conditions facilitating MBI of CYPs by the reactive epoxide metabolite are reported. The rate-determining step for the overall metabolic pathway leading to MBI was observed to be the initial epoxidation, requiring â¼12 kcal/mol under the enzymatic conditions. The covalent adducts (inactivator complexes) are highly stable (â¼-46 to -70 kcal/mol) and may be formed due to the reaction between furan epoxide and nucleophilic amino acid residues such as serine/threonine, preferably after initial activation by basic amino acids.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Compuestos Epoxi/farmacología , Furanos/farmacología , Dominio Catalítico , Sistema Enzimático del Citocromo P-450/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Compuestos Epoxi/química , Compuestos Epoxi/metabolismo , Furanos/química , Furanos/metabolismo , Hidrólisis , Modelos Moleculares , Teoría Cuántica , Agua/metabolismoRESUMEN
Cancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of -11.202 to -9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was -4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations.Communicated by Ramaswamy H. Sarma.
RESUMEN
BACKGROUND: Indoline-2,3-dione comprises a leading course group of heterocycles endowed with appealing biological actions, including anticancer activity. There are significant justifications for exploring the anticancer activity of Schiff base derivatives of isatin as a vast number of reports have documented remarkable antiproliferative action of isatin nucleus against various cancer cell lines. AIMS AND OBJECTIVES: A series of arylthiazole linked 2H-indol-2-one derivatives (5a-t) was designed and synthesized as potential VEGFR-2 kinase inhibitors keeping the essential pharmacophoric features of standard drugs, like sunitinib, sorafenib, nintedanib, etc. They were evaluated for their in vitro anticancer activity. The aim of this study was to investigate and assess the anticancer potential of isatin-containing compounds along with their kinase inhibition activity. METHODS: The title compounds were synthesized by reacting substituted isatins with para-substituted arylthiazoles using appropriate reaction conditions. Selected synthesized derivatives went under preliminary screening against a panel of 60 cancer cell lines at NCI, the USA, for single-dose and five dose assays. Molecular docking was performed to explore the binding and interactions with the active sites of the VEGFR-2 receptor (PDB Id: 3VHE). Derivatives 5a, 5b, 5c, 5d, 5g, 5h, and 5m were assessed for in vitro inhibition potency against Human VEGFR-2 using ELISA (Enzyme- Linked Immunosorbent Assay) kit. All the target compounds were determined against human colon cancer cell line SW480 (colorectal adenocarcinoma cells). Cellular apoptosis/necrosis was determined by flow cytometry using annexin V-FITC. DNA content of the cells was analyzed by flow cytometry and the cycle distribution was quantified. RESULTS: Compounds 5a and 5g exhibited noteworthy inhibition during a five-dose assay against a panel of 60 cell lines with MID GI50 values of 1.69 and 1.54 µM, respectively. Also, both the lead compounds 5a and 5g demonstrated promising VEGFR-2 inhibitory activity with IC50 values of 5.43±0.95 and 9.63±1.32 µM, respectively. The aforesaid potent compounds were found effective against SW480 (colorectal adenocarcinoma cells) with IC50 values of 31.44 µM and 106.91 µM, respectively. Compound 5a was found to arrest the cell cycle at the G2/M phase, increasing apoptotic cell death. The docking study also supported VEGFR-2 inhibitory activity as both compounds 5a and 5g displayed promising binding and interactions with the active sites of VEGFR-2 receptor (PDB: 3VHE) with docking scores - 9.355 and -7.758, respectively. All the compounds obeyed Lipinski's rule of five. CONCLUSION: Indoline-2,3-dione and thiazole have huge potential to be considered a steer combination approach for developing promising kinase inhibitors as cancer therapeutics.
Asunto(s)
Adenocarcinoma , Antineoplásicos , Neoplasias Colorrectales , Isatina , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Isatina/farmacología , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial VascularRESUMEN
Despite the intensive research efforts towards antiviral drug against COVID-19, no potential drug or vaccines has not yet discovered. Initially, the binding site of COVID-19 main protease was predicted which located between regions 2 and 3. Structure-based virtual screening was performed through a hierarchal mode of elimination technique after generating a grid box. This led to the identification of five top hit molecules that were selected on the basis of docking score and visualization of non-bonding interactions. The docking results revealed that the hydrogen bonding and hydrophobic interactions are the major contributing factors in the stabilization of complexes. The docking scores were found between -7.524 and -6.711 kcal/mol indicating strong ligand-protein interactions. Amino acid residues Phe140, Leu141, Gly143, Asn142, Thr26, Glu166 and Thr190 (hydrogen bonding interactions) and Phe140, Cys145, Cys44, Met49, Leu167, Pro168, Met165, Val42, Leu27 and Ala191 (hydrophobic interactions) formed the binding pocket of COVID-19 main protease. From identified hits, ZINC13144609 and ZINC01581128 were selected for atomistic MD simulation and density functional theory calculations. MD simulation results confirm that the protein interacting with both hit molecules is stabilized in the chosen POPC lipid bilayer membrane. The presence of lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) in the hydrophobic region of the hit molecules leads to favorable ligand-protein contacts. The calculated pharmacokinetic descriptors were found to be in their acceptable range and therefore confirming their drug-like properties. Hence, the present investigation can serve as the basis for designing and developing COVID-19 inhibitors. Communicated by Ramaswamy H. Sarma.
Asunto(s)
COVID-19 , Simulación de Dinámica Molecular , Teoría Funcional de la Densidad , Humanos , Simulación del Acoplamiento Molecular , SARS-CoV-2RESUMEN
INTRODUCTION: Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. Natural resources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment. METHODS: Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-based QSAR. RESULTS: The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity. CONCLUSION: These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at a low cost.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Naftoquinonas/química , Piruvato Quinasa/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Isoenzimas/antagonistas & inhibidoresRESUMEN
Angiotensin-converting enzyme 2 (ACE 2) is a membrane-bound enzyme that cleaves angiotensin II (Ang II) into angiotensin (1-7). It also serves as an important binding site for SARS-CoV-2, thereby, facilitating viral entry into target host cells. ACE 2 is abundantly present in the intestine, kidney, heart, lungs, and fetal tissues. Fetal ACE 2 is involved in myocardium growth, lungs and brain development. ACE 2 is highly expressed in pregnant women to compensate preeclampsia by modulating angiotensin (1-7) which binds to the Mas receptor, having vasodilator action and maintain fluid homeostasis. There are reports available on Zika, H1N1 and SARS-CoV where these viruses have shown to produce fetal defects but very little is known about SARS-CoV-2 involvement in pregnancy, but it might have the potential to interact with fetal ACE 2 and enhance COVID-19 transmission to the fetus, leading to fetal morbidity and mortality. This review sheds light on a path of SARS-CoV-2 transmission risk in pregnancy and its possible link with fetal ACE 2.
Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/epidemiología , Pandemias , Placenta/virología , Receptores Virales/genética , Glicoproteína de la Espiga del Coronavirus/genética , Adulto , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/diagnóstico , COVID-19/mortalidad , COVID-19/virología , Femenino , Mortalidad Fetal/tendencias , Feto , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Humanos , Riñón/virología , Modelos Moleculares , Embarazo , Estructura Secundaria de Proteína , Receptores Virales/química , Receptores Virales/metabolismo , Sistema Renina-Angiotensina/genética , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Útero/virologíaRESUMEN
Heterocyclic compounds play a significant role in various biological processes of the human body and many of them are in clinical use due to their diverse, chemical and biological properties. Among these, indole is one of the most promising pharmacologically active molecules. Due to its chemical reactivity, indole has been willingly modified to obtain a variety of new lead molecules, which has been successfully utilized to obtained novel drug candidates for the treatment of different pharmacological diseases. Indole-based compounds such as vincristine (anticancer), reserpine (antihypertensive), amedalin (antidepressant) and many more describe the medicinal and pharmacological importance of the indole in uplifting human life. In this review, we compiled various reports on indole derivatives and their biological significance, including antifungal, antiprotozoal, antiplatelet, anti- Alzheimer's, anti-Parkinson's, antioxidant and anticancer potential from 2015 onwards. In addition, structure-activity relationship studies of the different derivatives have been included. We have also discussed novel synthetic strategies developed during this period for the synthesis of different indole derivatives. We believe that this review article will provide comprehensive knowledge about the medicinal importance of indoles and will help in the design and synthesis of novel indole-based molecules with high potency and efficacy.
Asunto(s)
Indoles/química , Indoles/farmacología , Relación Estructura-Actividad , Enfermedad de Alzheimer/tratamiento farmacológico , Antiinfecciosos/síntesis química , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antioxidantes/síntesis química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Humanos , Indoles/uso terapéutico , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéuticoRESUMEN
The current global health threat by the novel coronavirus disease 2019 (COVID-19) requires an urgent deployment of advanced therapeutic options available. The role of nanotechnology is highly relevant to counter this "virus" nano enemy. Nano intervention is discussed in terms of designing effective nanocarriers to counter the conventional limitations of antiviral and biological therapeutics. This strategy directs the safe and effective delivery of available therapeutic options using engineered nanocarriers, blocking the initial interactions of viral spike glycoprotein with host cell surface receptors, and disruption of virion construction. Controlling and eliminating the spread and reoccurrence of this pandemic demands a safe and effective vaccine strategy. Nanocarriers have potential to design risk-free and effective immunization strategies for severe acute respiratory syndrome coronavirus 2 vaccine candidates such as protein constructs and nucleic acids. We discuss recent as well as ongoing nanotechnology-based therapeutic and prophylactic strategies to fight against this pandemic, outlining the key areas for nanoscientists to step in.
Asunto(s)
Infecciones por Coronavirus/prevención & control , Vacunación Masiva/métodos , Nanotecnología/métodos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales/uso terapéutico , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Humanos , Vacunación Masiva/efectos adversos , Neumonía Viral/inmunología , Neumonía Viral/terapia , Neumonía Viral/virología , Vacunas Virales/inmunologíaRESUMEN
Imidazole-based epidermal growth factor receptor (EGFR) inhibitors were computationally designed and synthesized. All the compounds were assessed for their anti-proliferative activity against five cancer cell lines, viz., MDA-MB-231 (breast), T47D (breast) and MCF-7 (breast), A549 (lung) and HT-29 (colorectal). Compounds 2c and 2d emerged as better anticancer molecules with no toxicity towards normal cells. 2c and 2d inhibited EGFR enzymatic activity in vitro with IC50 values of 617.33 ± 0.04 nM and 710 ± 0.05 nM, respectively. In order to further improve the potency, we explored an unoccupied area of the ATP binding domain of EGFR and analysed an in silico interaction model of 2c and 2d-EGFR complexes that guided and allowed substitution of the 4-fluorophenyl ring (2c and 2d) with 4-(4-methylpiperazinyl)-3-nitrophenyl at the N-9 position, resulting in compound 3c with a better binding score and potent EGFR inhibitory activity (IC50: 236.38 ± 0.04 nM), which was comparable to the positive control erlotinib (239.91 ± 0.05 nM). 3c exhibited a great improvement in anticancer potency with inhibition of cell growth of all cancer cell lines at very low micromolar concentrations (IC50 = 1.98 to 4.07 µM). Further investigation revealed that 3c also induced an increase in ROS levels in cancer cells in a mitochondrial-independent manner and halted the cell cycle at the sub-G1 phase.
RESUMEN
After restricting the proliferation of CD4+T cells, Human Immunodeficiency Virus (HIV), infection persists at a very fast rate causing Acquired Immunodeficiency Syndrome (AIDS). This demands the vigorous need of suitable anti-HIV agents, as existing medicines do not provide a complete cure and exhibit drawbacks like toxicities, drug resistance, side-effects, etc. Even the introduction of Highly Active Antiretroviral Therapy (HAART) failed to combat HIV/AIDS completely. The major breakthrough in anti-HIV discovery was marked with the discovery of raltegravir in 2007, the first integrase (IN) inhibitor. Thereafter, the discovery of elvitegravir, a quinolone derivative emerged as the potent HIV-IN inhibitor. Though many more classes of different drugs that act as anti-HIV have been identified, some of which are under clinical trials, but the recent serious focus is still laid on quinoline and its analogues. In this review, we have covered all the quinoline-based derivatives that inhibit various targets and are potential anti-HIV agents in various phases of the drug discovery.