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1.
Molecules ; 26(22)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34834088

RESUMO

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 µM, 15 µM, and 30 µM. The IC50 of calycosin is 30.35 µM, which is lower than hydroquinone (37.35 µM), kojic acid (6.51 × 103 µM), and arbutin (3.67 × 104 µM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.

2.
Front Immunol ; 12: 713276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34526989

RESUMO

Autoreactive CD8+ T cells play an indispensable key role in the destruction of pancreatic islet ß-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential ß-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA2-10) is an immunodominant ligand for autoreactive CD8+ T cells in NOD.ß2mnull .HHD mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses via triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA2-10, named mInsA2-10DQ4 and mInsA2-10DC6, respectively. We found that administration of mInsA2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.ß2mnull .HHD mice. Mechanistically, treatment with mInsA2-10DQ4 not only notably eliminated mInsA2-10 autoreactive CD8+ T cell responses but also prevented the infiltration of CD4+ T and CD8+ T cells, as well as the inflammatory responses in the pancreas of NOD.ß2mnull.HHD mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.

3.
Small ; 17(42): e2104445, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34558186

RESUMO

Double-atom catalyst (DAC) has gained much interest for its versatile tuning and synergistic effect of dual-atom active sites. Metal (M)-metal (M) diatomic sites, either homo- or heteronuclear, are typically researched. Hybrid metal-non-metal combined sites have rarely been studied and even the viability of such active sites are unknown. Herein, CO2 electroreduction (CO2 RR) is explored on M@X-C2 N (M = Fe, Co, Ni, and Cu; X = S, P, and B) which renders naturally generated M-X diatomic site. Using spin-polarized density functional theory coupled with computational hydrogen electrode model, it is demonstrated that the functionality of hybrid M-B dual-atom center is superior over that of a single- or double-M center in driving CO2 RR especially C-C coupling. Among metal-boron DACs studies, Fe@B-C2 N (µ = 2µB ) exhibits the lowest free energy barrier of 0.17 eV in C-C coupling whereas Ni@B-C2 N (µ = 0µB ) mainly produces CH4 with the lowest barrier of 0.42 eV. Hence, the electronic spin state of M can be particularly important in modulating selectivity and C-C coupling barrier in CO2 RR. Fe@B-C2 N is predicted as the promising catalyst for CO2 RR towards C2+ products owing partially to its enhanced spin state. The findings can enrich the design strategy of electrocatalysts normally running at ambient conditions.

4.
ACS Appl Mater Interfaces ; 13(24): 27856-27867, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34110146

RESUMO

Combining photodynamic therapy (PDT), chemodynamic therapy (CDT), and ferroptosis is a valuable means for an enhanced anticancer effect. However, traditional combination of PDT/CDT/ferroptosis faces several hurdles, including excess glutathione (GSH) neutralization and preparation complexity. In this work, a versatile multifunctional nanoparticle (HCNP) self-assembled from two porphyrin molecules, chlorin e6 and hemin, is developed. The as-constructed HCNPs exhibit a peroxidase-mimic catalytic activity, which can lead to the in situ generation of endogenous O2, thereby enhancing the efficacy of PDT. Furthermore, the generation of hydroxyl radicals (•OH) in the tumor environment in reaction to the high level of H2O2 and the simultaneous disruption of intracellular GSH endow the HCNPs with the capacity of enhanced CDT, resulting in a more effective therapeutic outcome in combination with PDT. More importantly, GSH depletion further leads to the inactivation of GSH peroxide 4 and induced ferroptosis. Both in vitro and in vivo results showed that the combination of PDT/CDT/ferroptosis realizes highest antitumor efficacy significantly under laser irradiation. Therefore, by integrating the superiorities of O2 and •OH generation capacity, GSH-depletion effect, and bioimaging into a single nanosystem, the HCNPs are a promising single therapeutic agent for tumor PDT/CDT/ferroptosis combination therapy.


Assuntos
Antineoplásicos/uso terapêutico , Hemina/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Catálise , Linhagem Celular Tumoral , Feminino , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Hemina/química , Hemina/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana , Humanos , Radical Hidroxila/metabolismo , Luz , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/efeitos da radiação , Oxigênio/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Porfirinas/química , Porfirinas/efeitos da radiação
5.
ACS Med Chem Lett ; 12(5): 758-767, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34055223

RESUMO

TRPM8 antagonists derived from its cognate ligand, (-)-menthol, are underrepresented. We determine the absolute stereochemistry of a well-known TRPM8 antagonist, (-)-menthyl 1, using VCD and 2D NMR. We explore 1 for its antagonist effects of the human TRPM8 (hTRPM8) orthologue to uncover species-dependent inhibition versus rat channels. (-)-Menthyl 1 inhibits menthol- and icilin-evoked Ca2+ responses at hTRPM8 with IC50 values of 805 ± 200 nM and 1.8 ± 0.6 µM, respectively, while more potently inhibiting agonist responses at the rat orthologue (rTRPM8 IC50 (menthol) = 117 ± 18 nM, IC50 (icilin) = 521 ± 20 nM). Whole-cell patch-clamp recordings of hTRPM8 confirm the 1 inhibition of menthol-stimulated currents, with an IC50 of 700 ± 200 nM. We demonstrate that 1 possesses ≥400-fold selectivity for hTRPM8 versus hTRPA1/hTRPV1. (-)-menthyl 1 can be used as a novel chemical tool to study hTRPM8 pharmacology and differences in species commonly used in drug discovery.

6.
Brief Bioinform ; 22(5)2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-33876197

RESUMO

The design of therapeutic antibodies has attracted a large amount of attention over the years. Antibodies are widely used to treat many diseases due to their high efficiency and low risk of adverse events. However, the experimental methods of antibody design are time-consuming and expensive. Although computational antibody design techniques have had significant advances in the past years, there are still some challenges that need to be solved, such as the flexibility of antigen structure, the lack of antibody structural data and the absence of standard antibody design protocol. In the present work, we elaborated on an in silico antibody design protocol for users to easily perform computer-aided antibody design. First, the Rosetta web server will be applied to generate the 3D structure of query antibodies if there is no structural information available. Then, two-step docking will be used to identify the binding pose of an antibody-antigen complex when the binding information is unknown. ClusPro is the first method to be used to conduct the global docking, and SnugDock is applied for the local docking. Sequentially, based on the predicted binding poses, in silico alanine scanning will be used to predict the potential hotspots (or key residues). Finally, computational affinity maturation protocol will be used to modify the structure of antibodies to theoretically increase their affinity and stability, which will be further validated by the bioassays in the future. As a proof of concept, we redesigned antibody D44.1 and compared it with previously reported data in order to validate IsAb protocol. To further illustrate our proposed protocol, we used cemiplimab antibody, a PD-1 checkpoint inhibitor, as an example to showcase a step-by-step tutorial.


Assuntos
Anticorpos/química , Complexo Antígeno-Anticorpo/química , Biologia Computacional/métodos , Desenho Assistido por Computador , Simulação de Acoplamento Molecular , Domínios Proteicos , Animais , Anticorpos/metabolismo , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/metabolismo , Especificidade de Anticorpos , Complexo Antígeno-Anticorpo/metabolismo , Sítios de Ligação de Anticorpos , Simulação por Computador , Cristalografia por Raios X , Humanos , Receptor de Morte Celular Programada 1/química , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica
7.
Comput Biol Chem ; 88: 107328, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32688011

RESUMO

Glycogen Synthase Kinase 3 (GSK-3) is a member of cellular kinase with various functions, such as glucose regulation, cellular differentiation, neuronal function and cell apoptosis. It has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. To better understand their structure-activity relationships and mechanism of action, an integrated computational study, including three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD), was performed on 79 (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine GSK-3 inhibitors. In this paper, we constructed 3D-QSAR using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) method. The results showed that the CoMFA model (q2 = 0.743,  r2 = 0.980) and the CoMSIA model (q2 = 0.813,  r2 = 0.976) had stable and reliable predictive ability. The electrostatic and H-bond donor fields play important roles in the models. The contour maps of the model visually showed the relationship between the activity of compounds and their three-dimensional structure. Molecular docking was used to identify the key amino acid residues at the active site of GSK-3 and explore its binding mode with ligands. Based on 3D-QSAR models, contour maps and the binding feature between GSK-3 and inhibitor, we designed 10 novel compounds with good potential activity and ADME/T profile. Molecular dynamics simulation results validated that Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. These results might provide important information for designing GSK-3 inhibitors with high activity.


Assuntos
Aminas/farmacologia , Desenho de Fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Aminas/síntese química , Aminas/química , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química
8.
J Colloid Interface Sci ; 573: 78-86, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32259694

RESUMO

Inorganic p-type materials show great potential as the hole transport layer in perovskite solar cells with the merits of low costs and enhanced chemical stability. As a p-type material, cobalt oxide (CoO) has received so far not that level of attention despite its high hole mobility. Herein, solution-processed p-type CoO nanocrystalline films are developed for inverted mixed perovskite solar cells. The ultrafine CoO nanocrystals are synthesized via an oil phase method, which are subsequently treated by a ligand exchange process using pyridine solvent to remove the long alkyl chains covering the nanocrystals. From this homogeneous colloidal solution CoO films are obtained, which exhibit a smooth and pin-hole free surface morphology with high transparency and good conductivity. The ultraviolet photoelectron spectrum also indicates that the energy levels of the CoO film match well with the mixed perovskite Cs0.05(FA0.83MA0.17)0.95(I0.83Br0.17)3. Inverted solar cells based on crystalline CoO films with ligand exchange show a reasonable energy conversion efficiency, whereas devices based on CoO films without ligand exchange suffer from a strong S-shape JV-characteristic. Thus, the crystalline CoO films are foreseen to pave a new way of inorganic hole transport materials in the fields of perovskite solar cells.

9.
ACS Omega ; 5(5): 2428-2439, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32064403

RESUMO

Epilepsy is a common cause of serious cognitive disorders and is known to have impact on patients' memory and executive functions. Therefore, the development of antiepileptic drugs for the improvement of spatial learning and memory in patients with epileptic cognitive dysfunction is important. In the present work, we systematically predicted and analyzed the potential effects of Ginkgo terpene trilactones (GTTL) on cognition and pathologic changes utilizing in silico and in vivo approaches. Based on our established chemogenomics knowledgebase, we first conducted the network systems pharmacology analysis to predict that ginkgolide A/B/C may target 5-HT 1A, 5-HT 1B, and 5-HT 2B. The detailed interactions were then further validated by molecular docking and molecular dynamics (MD) simulations. In addition, status epilepticus (SE) was induced by lithium-pilocarpine injection in adult Wistar male rats, and the results of enzyme-linked immunosorbent assay (ELISA) demonstrated that administration with GTTL can increase the expression of brain-derived neurotrophic factor (BDNF) when compared to the model group. Interestingly, recent studies suggest that the occurrence of a reciprocal involvement of 5-HT receptor activation along with the hippocampal BDNF-increased expression can significantly ameliorate neurologic changes and reverse behavioral deficits in status epilepticus rats while improving cognitive function and alleviating neuronal injury. Therefore, we evaluated the effects of GTTL (bilobalide, ginkgolide A, ginkgolide B, and ginkgolide C) on synergistic antiepileptic effect. Our experimental data showed that the spatial learning and memory abilities (e.g., electroencephalography analysis and Morris water maze test for behavioral assessment) of rats administrated with GTTL were significantly improved under the middle dose (80 mg/kg, GTTL) and high dose (160 mg/kg, GTTL). Moreover, the number of neurons in the hippocampus of the GTTL group increased when compared to the model group. Our studies showed that GTTL not only protected rat cerebral hippocampal neurons against epilepsy but also improved the learning and memory ability. Therefore, GTTL may be a potential drug candidate for the prevention and/or treatment of epilepsy.

10.
J Biomol Struct Dyn ; 38(15): 4567-4578, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31760877

RESUMO

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is one of the most attractive drug targets for the treatment of AIDS. In this study, 67 thieno[3,4-d]pyrimidine derivatives were selected as novel HIV-1 RT inhibitors to combat viral resistance, and were subjected to 3 D-QSAR studies using CoMFA, CoMSIA, and T-CoMFA. In the 3 D-QSAR study, two methods of ligand-based alignment and pharmacophore-based alignment were used. The results showed that CoMFA (n = 8; q2 = 0.594; r2 = 0.974) and CoMSIA (n = 7; q2 = 0.528; r2 = 0.965) have good stability and predictability. The molecular docking study showed that the hydrogen bonding and van der Waals interactions of key residues such as Leu100, Lys101, Val106, Phe227 and Pro236 play an important role in ligand-receptor binding. Based on these results, 12 new thieno[3,4-d]pyrimidines were designed and their activities were predicted; the results indicated that these compounds have good predictive activity and reasonably good ADME/T profiles. MD simulation analysis of 50 ns showed that compound 23j formed four hydrogen bonds with the residues (Lys101, Lys104, Val106 and Thr318), and binds more closely to HIV-1 RT than compound 23j. Furthermore, the group at the R1 position and the horseshoe-like conformation of these compounds are critical for the inhibitory activity and stability. These results provide useful insights for the discovery and design of a new generation of HIV-1 RT inhibitors.Communicated by Ramaswamy H. Sarma.


Assuntos
HIV-1 , Relação Quantitativa Estrutura-Atividade , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pirimidinas
12.
ACS Chem Neurosci ; 11(3): 268-290, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31850745

RESUMO

Structure-activity relationship studies of a reported menthol-based transient receptor potential cation channel subfamily M member 8 channel (TRPM8) antagonist, guided by computational simulations and structure-based design, uncovers a novel series of TRPM8 antagonists with >10-fold selectivity versus related TRP subtypes. Spiro[4.5]decan-8-yl analogue 14 inhibits icilin-evoked Ca2+ entry in HEK-293 cells stably expressing human TRPM8 (hTRPM8) with an IC50 of 2.4 ± 1.0 nM, while in whole-cell patch-clamp recordings this analogue inhibits menthol-evoked currents with a hTRPM8 IC50 of 64 ± 2 nM. Molecular dynamics (MD) simulations of compound 14 in our homology model of hTRPM8 suggest that this antagonist forms extensive hydrophobic contacts within the orthosteric site. In the wet dog shakes (WDS) assay, compound 14 dose-dependently blocks icilin-triggered shaking behaviors in mice. Upon local administration, compound 14 dose dependently inhibits cold allodynia evoked by the chemotherapy oxaliplatin in a murine model of peripheral neuropathy at microgram doses. Our findings suggest that 14 and other biphenyl amide analogues within our series can find utility as potent antagonist chemical probes derived from (-)-menthol as well as small molecule therapeutic scaffolds for chemotherapy-induced peripheral neuropathy (CIPN) and other sensory neuropathies.


Assuntos
Compostos de Bifenilo/antagonistas & inibidores , Hiperalgesia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Relação Estrutura-Atividade , Canais de Cátion TRPM/metabolismo , Amidas , Cálcio/metabolismo , Células HEK293 , Humanos , Mentol/análogos & derivados , Técnicas de Patch-Clamp/métodos , Canais de Cátion TRPM/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/efeitos dos fármacos , Canais de Potencial de Receptor Transitório/metabolismo
13.
Molecules ; 24(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640203

RESUMO

The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1-PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein-protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1-PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1.


Assuntos
Receptor de Morte Celular Programada 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Simulação por Computador , Humanos , Conformação Molecular , Simulação de Dinâmica Molecular , Receptor de Morte Celular Programada 1/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ressonância de Plasmônio de Superfície
14.
Molecules ; 24(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540429

RESUMO

Studies have indicated that Na+-d-glucose co-transporter (SGLT) inhibitors had anti-proliferative activity by attenuating the uptake of glucose in several tumor cell lines. In this study, the molecular docking showed that, trilobatin, one of the dihydrochalcones from leaves of Lithocarpus polystachyus Rehd., might be a novel inhibitor of SGLT1 and SGLT2, which evidently attenuated the uptake of glucose in vitro and in vivo. To our surprise, we observed that trilobatin did not inhibit, but promoted the proliferation of human hepatoblastoma HepG2 and Huh 7 cells when it was present at high concentrations. At the same time, incubation with high concentrations of trilobatin arrested the cell cycle at S phase in HepG2 cells. We also found that treatment with trilobatin had no significant effect on the expression of hepatitis B x-interacting protein (HBXIP) and hepatocyte nuclear factor (HNF)-4α, the two key regulators of hepatocyte proliferation. Taken together, although trilobatin worked as a novel inhibitor of SGLTs to attenuate the uptake of glucose, it also selectively induced the cell proliferation of HepG2 cells, suggesting that not all the SGLT inhibitors inhibited the proliferation of tumor cells, and further studies are needed to assess the anti-cancer potentials of new glucose-lowering agents.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Flavonoides , Células Hep G2 , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/metabolismo , Polifenóis , Ratos , Inibidores do Transportador 2 de Sódio-Glicose/química
15.
ACS Chem Neurosci ; 10(8): 3486-3499, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31257858

RESUMO

The United States of America is fighting against one of its worst-ever drug crises. Over 900 people a week die from opioid- or heroin-related overdoses, while millions more suffer from opioid prescription addiction. Recently, drug overdoses caused by fentanyl-laced cocaine specifically are on the rise. Due to drug synergy and an increase in side effects, polydrug addiction can cause more risk than addiction to a single drug. In the present work, we systematically analyzed the overdose and addiction mechanism of cocaine and fentanyl. First, we applied our established chemogenomics knowledgebase and machine-learning-based methods to map out the potential and known proteins, transporters, and metabolic enzymes and the potential therapeutic target(s) for cocaine and fentanyl. Sequentially, we looked into the detail of (1) the addiction to cocaine and fentanyl by binding to the dopamine transporter and the µ opioid receptor (DAT and µOR, respectively), (2) the potential drug-drug interaction of cocaine and fentanyl via p-glycoprotein (P-gp) efflux, (3) the metabolism of cocaine and fentanyl in CYP3A4, and (4) the physiologically based pharmacokinetic (PBPK) model for two drugs and their drug-drug interaction at the absorption, distribution, metabolism, and excretion (ADME) level. Finally, we looked into the detail of JWH133, an agonist of cannabinoid 2-receptor (CB2) with potential as a therapy for cocaine and fentanyl overdose. All these results provide a better understanding of fentanyl and cocaine polydrug addiction and future drug abuse prevention.


Assuntos
Cocaína , Overdose de Drogas , Fentanila , Aprendizado de Máquina , Transtornos Relacionados ao Uso de Opioides , Analgésicos Opioides , Cocaína/efeitos adversos , Cocaína/metabolismo , Cocaína/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Simulação por Computador , Overdose de Drogas/metabolismo , Fentanila/efeitos adversos , Fentanila/metabolismo , Fentanila/farmacologia , Humanos
16.
Comput Biol Chem ; 80: 234-243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009872

RESUMO

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R2>0.75) and predictability (Q2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica II/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Conjuntos de Dados como Assunto , Desenho de Fármacos , Humanos , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
17.
Acta Pharmacol Sin ; 40(9): 1138-1156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30814658

RESUMO

Serotonin (5-HT) receptors are proteins involved in various neurological and biological processes, such as aggression, anxiety, appetite, cognition, learning, memory, mood, sleep, and thermoregulation. They are commonly associated with drug abuse and addiction due to their importance as targets for various pharmaceutical and recreational drugs. However, due to a high sequence similarity/identity among 5-HT receptors and the unavailability of the 3D structure of the different 5-HT receptor, no report was available so far regarding the systematical comparison of the key and selective residues involved in the binding pocket, making it difficult to design subtype-selective serotonergic drugs. In this work, we first built and validated three-dimensional models for all 5-HT receptors based on the existing crystal structures of 5-HT1B, 5-HT2B, and 5-HT2C. Then, we performed molecular docking studies between 5-HT receptors agonists/inhibitors and our 3D models. The results from docking were consistent with the known binding affinities of each model. Sequentially, we compared the binding pose and selective residues among 5-HT receptors. Our results showed that the affinity variation could be potentially attributed to the selective residues located in the binding pockets. Moreover, we performed MD simulations for 12 5-HT receptors complexed with ligands; the results were consistent with our docking results and the reported data. Finally, we carried out off-target prediction and blood-brain barrier (BBB) prediction for Captagon using our established hallucinogen-related chemogenomics knowledgebase and in-house computational tools, with the hope to provide more information regarding the use of Captagon. We showed that 5-HT2C, 5-HT5A, and 5-HT7 were the most promising targets for Captagon before metabolism. Overall, our findings can provide insights into future drug discovery and design of medications with high specificity to the individual 5-HT receptor to decrease the risk of addiction and prevent drug abuse.


Assuntos
Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Sítios de Ligação , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Farmacologia/métodos , Receptores de Serotonina/química , Antagonistas da Serotonina/química , Agonistas do Receptor de Serotonina/química
18.
J Mol Model ; 24(9): 243, 2018 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-30121710

RESUMO

Paracetamol is a relatively safe analgesia/antipyretic drug without the risks of addiction, dependence, tolerance, and withdrawal when used alone. However, when administrated in an opioid/paracetamol combination product, which often contains a large quantity of paracetamol, it can be potentially dangerous due to the risk of hepatotoxicity. Paracetamol is known to be metabolized into N-(4-hydroxyphenyl)-arachidonamide (AM404) via fatty acid amide hydrolase (FAAH) and into N-acetyl-p-benzoquinone imine (NAPQI) via cytochrome P450 (CYP) enzymes. However, the underlying mechanism of paracetamol is still unclear. In addition, paracetamol has the potential to interact with other drugs that are also involved with CYP family enzymes (inducer/inhibitor/substrate), an example being illicit drugs. In our present work, we looked into the relationship between paracetamol and its metabolites (AM404 and NAPQI) using molecular docking and molecular dynamics (MD) simulations. We first carried out a series of molecular docking studies between paracetamol/AM404/NAQPI and their reported targets, including CYP 2E1, FAAH, TRPA1, CB1, and TRPV1. Subsequently, we performed MD simulations and energy decomposition for CB1-AM404, TRPV1-AM404, and TRPV1-NAPQI for further investigation of the dynamics interactions. Finally, we summarized and discussed the reported drug-drug interactions between paracetamol and central nervous system drugs, especially illicit drugs. Overall, we are able to provide new insights into the structural and functional roles of paracetamol and its metabolites that can inform the potential prevention and treatment of paracetamol overdose. Graphical abstract Paracetamol and its metabolites.

19.
Int J Biol Sci ; 14(10): 1389-1398, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123084

RESUMO

It has been reported that overactivation of fibroblast growth factor receptor 1 (FGFR1) is an important characteristic found in most non-small cell lung cancer (NSCLC) samples. Here, we identified a FGFR1 inhibitory peptide R1-P2 and investigated its effects on the lung cancer cells growth and angiogenesis in vitro and in vivo. Our results demonstrate that R1-P2 bound to human FGFR1 protein, and efficiently blocked the binding of FGF2 to FGFR1 in A549 and NCI-H460 cells. Moreover, this peptide significantly decreased the proliferation, migration and invasion, but promoted the apoptosis in both cell lines. In addition, R1-P2 treatment effectively inhibited the tumor growth and neovascularization in nude mice with xenografted A549 cells, and R1-P2 also significantly inhibited the FGF2-induced angiogenesis in tube formation experiment and CAM model. We further demonstrated that R1-P2 suppressed lung tumor growth through anti-angiogenic and anti-proliferative activity. Our data may provide a novle leading molecule with potential application in the treatment of FGFR1 activation related lung cancers.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neovascularização Patológica/tratamento farmacológico , Peptídeos/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Células A549 , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Neovascularização Patológica/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Mol Biosyst ; 12(11): 3396-3406, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27714030

RESUMO

CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), plays a vital role in inflammatory responses to infection. Alterations in the expression of CCR5 have been correlated with disease progression in many types of cancers. The idea of using CCR5 as a target for therapeutic intervention has been demonstrated to prevent disease progression. To date, only a few compounds have been reported as CCR5 inhibitors. In this study, a series of CCR5 antagonists were used to construct pharmacophore models. Then the optimal model was utilized as a 3D query to identify novel chemical entities from structural databases. After refinement by molecular docking, drug-likeness analysis, molecular dynamics simulations (MDS) and binding free energy analysis, three potential inhibitors (25, 29 and 45) were identified. MD simulations suggested that the screened compounds retained the important common binding mode known for CCR5 inhibitors (maraviroc and nifeviroc), which occupied the bottom of a pocket and stabilized the conformation of CCR5. During the binding process, van der Waals interactions provided the substantial driving force. The most favorable contributions were from Tyr37, Trp86, Tyr89, Tyr108, Phe109, Phe112, Gln194, Thr195, Ile198, Trp248, Tyr251, Leu255, Thr259, Met279, Glu283 and Met287. The above results suggest that the hybrid strategy would provide a basis for rational drug design.


Assuntos
Antagonistas dos Receptores CCR5/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptores CCR5/química , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Desenho de Fármacos , Ligantes , Conformação Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
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