RESUMEN
Background: Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. Methodology & results: The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC50 against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity in vitro studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. Conclusion: The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.
Asunto(s)
Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ligandos , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Medicinal plants are well-known in affording clinically useful agents, with rich medicinal values by combining with disease targets through various mechanisms. Plant secondary metabolites as lead compounds lay the foundation for the discovery and development of new drugs in disease treatment. Genus Uncaria from Rubiaceae family is a significant plant source of active alkaloids, with anti-hypertensive, sedative, anti-Alzheimer's disease, anti-drug addiction and anti-inflammatory effects. This review summarizes and discuss the research progress of Uncaria based on alkaloids in the past 15 years, mainly in the past 5 years, including biosynthesis, phytochemistry, pharmacology and structural chemistry. Among, focusing on representative compounds rhynchophylline and isorhynchophylline, the pharmacological activities surrounding the central nervous system and cardiovascular system are described in detail. On the basis of case studies, this article provides a brief overview of the synthesis and analogues of representative compounds types. In summary, this review provides an early basis for further searching for new targets and activities, discussing the mechanisms of pharmacological activity and studying the structure-activity relationships of active molecules.
Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Uncaria/química , Alcaloides/metabolismo , Animales , Vías Biosintéticas , Descubrimiento de Drogas , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/farmacología , Humanos , Oxindoles/química , Oxindoles/metabolismo , Oxindoles/farmacología , Uncaria/metabolismoRESUMEN
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Imidazoles/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Isoindoles/farmacología , Tiofenos/farmacología , Enfermedad de Alzheimer/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/síntesis química , Imidazoles/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Isoindoles/síntesis química , Isoindoles/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC50 = 0.18 ± 0.03 µM, hBChE IC50 = 0.32 ± 0.07 µM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aß1-42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aß1-42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T1/2, and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.
Asunto(s)
Aminoquinolinas/farmacología , Bencimidazoles/farmacología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Fármacos Neuroprotectores/farmacología , Aminoquinolinas/síntesis química , Aminoquinolinas/metabolismo , Aminoquinolinas/toxicidad , Animales , Bencimidazoles/síntesis química , Bencimidazoles/metabolismo , Bencimidazoles/toxicidad , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/toxicidad , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/toxicidad , Unión Proteica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/toxicidadRESUMEN
Designing small molecule inhibitors targeting cholinesterases (ChEs) is considered as an efficient strategy for the treatment of Alzheimer's disease (AD). In the present study, based on a shaped-based pharmacophore (SBP) model that we reported previously, virtual screening was performed on four commercial compound databases, from which eight small molecules containing new structurally scaffolds were retained and evaluated. In general, six of these potential hits were identified to be selective ChEs inhibitors. Three compounds exhibited IC50 values and Ki values in micromolar range on acetylcholinesterase (AChE), the most active compound 4 showed IC50 value of 6.31⯱â¯2.68⯵M and Ki value of 4.76⯵M. Other three compounds displayed IC50 values and Ki values in micromolar range on butyrylcholinesterase (BChE) with high target selectivity, the most active compound 1 showed IC50 value of 3.87⯱â¯2.48⯵M and Ki value of 1.52⯵M. Multiple biological evaluations were performed to determine their cytotoxicity, cyto-protective effects, antioxidant effect as well as druglike properties. These compounds provide new cores for the further design and optimization, with the aim to discover new ChEs inhibitors for the treatment of AD.
Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Descubrimiento de Drogas , Simulación de Dinámica Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Electrophorus , Células Hep G2 , Caballos , Humanos , Estructura Molecular , Células PC12 , Ratas , Relación Estructura-ActividadRESUMEN
Diabetes is one of the metabolic disorders in the world. It is the prime reason of mortality and morbidity owing to hyperglycemia which is link with numerus obstacles. Artemisia argyi is commonly used as an ingredient in healthy foods as well as an herbal medicine in Asian countries. The present research aims to evaluate the hypoglycemic effects of A. argyi and reveal its the potentially active constituents. The chemical composition was identified by HPLC-DAD-Q-TOF-MS, and fractionation was performed by extraction. The fractions were assessed by the blood glucose level, oral glucose tolerance and small intestinal α-glucosidase inhibitory tests, and an analysis of the total phenolic content (TPC), antioxidant and α-glucosidase inhibitory activities. In our efforts to characterize the compounds responsible for hypoglycemic effect, bioactivity-guided fraction of the MeOH extract and chemical investigation of its active EtOAc fraction led to the successful identification of caffeoylquinic acids, which were elucidated by molecular docking, using the crystal structure of S. cerevisiae isomaltase (PD code: 3AXI). In summary, this bio-guided search revealed that caffeoylquinic acids from A. argyi as potential active constituents displayed with hypoglycemic activity, which provided a basis for further study of pharmacological activity.
Asunto(s)
Antioxidantes/farmacología , Artemisia/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Extractos Vegetales/farmacología , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Benzotiazoles/antagonistas & inhibidores , Compuestos de Bifenilo/antagonistas & inhibidores , Glucemia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Recuperación de Fluorescencia tras Fotoblanqueo , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Hipoglucemiantes/química , Hipoglucemiantes/aislamiento & purificación , Intestino Delgado/enzimología , Masculino , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Estructura Molecular , Picratos/antagonistas & inhibidores , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Ácidos Sulfónicos/antagonistas & inhibidores , alfa-Glucosidasas/metabolismoRESUMEN
Streblus asper Lour. (Moraceae) is a medicinal plant in Asian countries including India and Thailand, possessing activities of anti-tumor, anti-allergy, anti-parasitic and anti-bacterial. In this paper, characterization, quantitation and similarity evaluation of cardiac glycosides in different parts of S. asper were investigated by HPLC-Q-TOF-MS and chemometric methods. Then, the inhibition of Na+,K+-ATPase activity by the compounds isolated from S. asper was measured. Meanwhile, enzyme kinetics and molecular docking were determined to exhibit the combination modes between cardiac glycosides and Na+,K+-ATPase. As a result, twenty peaks of cardiac glycosides were assigned. Strophanthidin-3-O-α-l-rhamnopyranosyl-(1â¯ââ¯4)-6-deoxy-ß-d-allopyranoside (1), glucostrebloside (2), strebloside (4) and mansonin (8) with a significant activity of inhibiting Na+,K+-ATPase (IC50 7.55-13.60⯵M) were chosen for the determination of enzyme kinetics, exhibiting anticompetitive inhibitory characteristics towards Na+,K+-ATPase. Compound 4 could reasonably bind to the active sites of Na+,K+-ATPase, proved by molecular docking. Furthermore, the contents of the major compounds in four different parts of S. asper were extremely different, analyzed by chemometric methods, similarity analysis and principle compounds analysis. All these findings indicated that the contents of major compounds in different parts of S. asper were extremely different with a significant activity of inhibiting Na+,K+-ATPase, providing a reference for determination of effective part and administered dosage. The combination modes between cardiac glycosides and Na+,K+-ATPase were also revealed by enzyme kinetics and molecular docking, which provided a basis for further study of pharmacological activity.
Asunto(s)
Glicósidos Cardíacos/farmacología , Inhibidores Enzimáticos/farmacología , Moraceae/química , Plantas Medicinales/química , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Animales , Glicósidos Cardíacos/química , Glicósidos Cardíacos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Conformación Molecular , Simulación del Acoplamiento Molecular , ATPasa Intercambiadora de Sodio-Potasio/química , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Relación Estructura-Actividad , PorcinosRESUMEN
Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer's disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC50 values in sub-micromolar range on eqBChE and three displayed IC50 values <â¯2⯵M on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD.
Asunto(s)
Butirilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/farmacocinética , Inhibidores de la Colinesterasa/toxicidad , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Electrophorus , Caballos , Humanos , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura MolecularRESUMEN
There is a growing interest in the exploitation of agricultural byproducts. This study explored the potential beneficial health effects from the main biowaste, tea seed pomace of Camellia oleifera Abel (Theaceae), produced when tea seed is processed. Eighteen compounds were isolated from the 70% EtOH extract of the seed cake of C. oleifera. Their structures were determined by ESI-MS, 1 H- and 13 C-NMR together with literature data. All fractions and compounds were evaluated for the antioxidant and melanogenesis inhibitory activities. As the result, AcOEt fraction has the best in vitro antioxidant and antimelanogenesis activities, compounds 7 - 12 and 15 showed remarkable antioxidant activity, compounds 4, 6, 8, and 15 - 17 exhibited superior inhibitory activities against melanogenesis. Furthermore, tyrosinase inhibitory activity assay suggested that compound 8 could suppress melanogenesis by inhibiting the expression of tyrosinase.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antioxidantes/farmacología , Camellia/química , Inhibidores Enzimáticos/farmacología , Melaninas/antagonistas & inhibidores , Monofenol Monooxigenasa/antagonistas & inhibidores , Extractos Vegetales/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Melaninas/metabolismo , Ratones , Estructura Molecular , Monofenol Monooxigenasa/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Semillas/química , Relación Estructura-ActividadRESUMEN
A new series of ortho-naphthoquinone analogs of ß-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to ß-lapachone. Thus avoiding the use of hydroxylpropyl ß-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0µmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with ß-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Naftoquinonas/química , Naftoquinonas/uso terapéutico , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Naftoquinonas/síntesis química , Naftoquinonas/metabolismo , Solubilidad , Agua/químicaRESUMEN
Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress-related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS-challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti-inflammatory agents through Nrf2-ARE pathway.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Diseño de Fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Oxadiazoles/química , Oxadiazoles/farmacología , Animales , Elementos de Respuesta Antioxidante/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Células HCT116 , Humanos , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Relación Estructura-Actividad , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 µM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.
Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células HCT116 , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.
Asunto(s)
Quinasa de la Caseína II/antagonistas & inhibidores , Diseño de Fármacos , Naftiridinas/química , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Interfaz Usuario-Computador , Quinasa de la Caseína II/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Fenazinas , Conformación Proteica , Programas InformáticosRESUMEN
Heat shock protein 90 (Hsp90), whose inhibitors have shown promising activity in clinical trials, is an attractive anticancer target. In this work, we first explored the significant pharmacophore features needed for Hsp90 inhibitors by generating a 3D-QSAR pharmacophore model. It was then used to virtually screen the SPECS databases, identifying 17 hits. Compound S1 and S13 exhibited the most potent inhibitory activity against Hsp90, with IC50 value 1.61±0.28 µM and 2.83±0.67 µM, respectively. Binding patterns analysis of the two compounds with Hsp90 revealed reasonable interaction modes. Further evaluation showed that the compounds exhibited good anti-proliferative effects against a series of cancer cell lines with high expression level of Hsp90. Meanwhile, S13 induced cell apoptosis in a dose-dependent manner in different cell lines. Based on the consideration of binding affinities, physicochemical properties and toxicities, 24 derivatives of S13 were designed, leading to the more promising compound S40, which deserves further optimization.
Asunto(s)
Simulación por Computador , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Ligandos , Relación Estructura-Actividad Cuantitativa , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Bases de Datos Factuales , Evaluación Preclínica de Medicamentos/métodos , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Unión ProteicaRESUMEN
A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides' structure-activity relationship (SAR).
Asunto(s)
Antibacterianos/síntesis química , Cetólidos/química , Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Sitios de Unión , Claritromicina/química , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Cetólidos/síntesis química , Cetólidos/farmacología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Peptidil Transferasas/química , Peptidil Transferasas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
IκB kinase ß (IKKß), an attractive anti-inflammation and anti-cancer target, plays a crucial role in the activation of NF-κB signalling pathway. To identify novel IKKß inhibitors, we combined structure-based and ligand-based methods based on the co-crystal structure of IKKß. According to the chemical similarity, 162 reported IKKß inhibitors were divided into five classes. For each class, a 3D pharmacophore model was established based on the binding conformations of the compounds. The validated models were further used in virtual screening. Twelve drugable compounds were retained for biological test, resulting in two novel inhibitors with IC50 values lower than 10 µM. Compared to other models, our method considers the crystal structure of IKKß for the first time.
Asunto(s)
Quinasa I-kappa B/química , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Estructura Terciaria de Proteína , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Ligandos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
Overexpression of ABCB1 is one of major barriers for multidrug resistance in chemotherapy and limits drug oral bioavailability. Inhibition of ABCB1 would sensitize multidrug resistance in clinical cancer chemotherapy. With this aim, a 3D pharmacophore model was created based on known ABCB1 inhibitors with correlation coefficient of 0.94, comprising three hydrophobic features and one hydrogen bond acceptor. It was further validated and used to search our in-house 3D database for potential ABCB1 inhibitors. The inhibitory activities of the best hits were evaluated by several biological assays, such as rhodamine 123 accumulation assay, chemosensitization assay, multidrug resistance 1-Madin-Darby canine kidney cells/Madin-Darby canine kidney cells permeability assay. Finally, compounds YZ-3 and YZ-16 were identified as potential leads to be developed in the designing of novel potent ABCB1 inhibitors.