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2.
Chem Biol Drug Des ; 94(4): 1824-1834, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31293023

RESUMO

Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8.

3.
Int J Biol Macromol ; 134: 28-35, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063788

RESUMO

Characterization and determination of protein-protein interactions (PPIs) plays an important role in molecular biological science. In this study, the effect of aminoglycosides (AGs: streptomycin, gentamycin, lincomycin and clindamycin) on interactions between bovine serum albumin (BSA) was evaluated employing imaging and probing adhesion event by AFM. Multi-spectroscopy and molecular docking were supplementary to investigate the acting forces of the effect. AFM measurements revealed the aggregation of BSA grains and changes of adhesion forces at single molecule level. With adhesion forces between BSA pairs decomposed by Poisson method, specific forces in streptomycin, gentamycin, lincomycin and climdamycin were obviously decreased with the rate of 33.1%, 26.4%, 32.3% and 31.3% while non-specific forces slightly decreased with 5.5%, 3.3%, 4.0% and 7.7%. Combined with results of multi-spectroscopy as well as molecular docking, the whole determination showed AGs affected PPIs by multiple forces, where the hydrogen bonding and hydration effect were the main reasons. The binding of drugs and proteins acted by hydrogen bonding affected the interaction forces between BSA. Consequently, AFM was proposed to be an effective and precise tool in application including evaluating the effects of exogenous compounds on biomacromolecular interactions and rapid screening of drug candidates to avoid potential damages in disease treatment.


Assuntos
Aminoglicosídeos/química , Microscopia de Força Atômica , Soroalbumina Bovina/química , Aminoglicosídeos/metabolismo , Animais , Sítios de Ligação , Bovinos , Ligações de Hidrogênio , Modelos Moleculares , Conformação Molecular , Mapeamento de Interação de Proteínas , Soroalbumina Bovina/metabolismo , Análise Espectral , Relação Estrutura-Atividade
4.
Dent Mater ; 35(7): 1031-1041, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076156

RESUMO

OBJECTIVE: Calcium phosphate cements (CPCs) mimic nanostructured bone minerals and are promising for dental, craniofacial and orthopedic applications. Vascularization plays a critical role in bone regeneration. This article represents the first review on cutting-edge research on prevascularization of CPC scaffolds to enhance bone regeneration. METHODS: This article first presented the prevascularization of CPC scaffolds. Then the co-culture of two cell types in CPC scaffolds was discussed. Subsequently, to further enhance the prevascularization efficacy, tri-culture of three different cell types in CPC scaffolds was presented. RESULTS: (1) Arg-Gly-Asp (RGD) incorporation in CPC bone cement scaffold greatly enhanced cell affinity and bone prevascularization; (2) By introducing endothelial cells into the culture of osteogenic cells (co-culture of two different cell types, or bi-culture) in CPC scaffold, the bone defect area underwent much better angiogenic and osteogenic processes when compared to mono-culture; (3) Tri-culture with an additional cell type of perivascular cells (such as pericytes) resulted in a substantially enhanced prevascularization of CPC scaffolds in vitro and more new bone and blood vessels in vivo, compared to bi-culture. Furthermore, biological cell crosstalk and capillary-like structure formation made critical contributions to the bi-culture system. In addition, the pericytes in the tri-culture system substantially promoted stability and maturation of the primary vascular network. SIGNIFICANCE: The novel approach of CPC scaffolds with stem cell bi-culture and tri-culture is of great significance in the regeneration of dental, craniofacial and orthopedic defects in clinical practice.


Assuntos
Cimentos para Ossos , Engenharia Tecidual , Fosfatos de Cálcio , Diferenciação Celular , Técnicas de Cocultura , Osteogênese , Células-Tronco , Tecidos Suporte
5.
Integr Biol (Camb) ; 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30855664

RESUMO

Binding/unbinding kinetics are key determinants of drug potencies. However, there are still a lot of challenges in predicting kinetic properties during early-stage drug development. In this work, position-restrained molecular dynamics simulations combined with energy decomposition were applied to extract protein-ligand interaction (PLI) fingerprints along the unbinding pathway of 20 p38 mitogen-activated protein kinase (p38 MAPK) Type II inhibitors. The results showed that the electrostatic and/or van der Waals interaction fingerprints at three key positions can be used for accurate prediction of the dissociation rate constants (koff) of p38 MAPK Type II inhibitors. The strategy proposed in this paper can provide not only an efficient method of predicting the dissociation rates of the p38 MAPK Type II inhibitors, but also the atom-level mechanism of enthalpy-driven unbinding process.

6.
Comput Struct Biotechnol J ; 17: 319-323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30899446

RESUMO

P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp. The results can be reconciled with a range of experimental studies, further corroborating the reliability of the gate revealed by computational simulations. Our atomic level description of the ligand access pathway provides valuable insights into the gating mechanism for drug uptake and transport by P-gp and other multidrug transporters.

7.
J Chem Inf Model ; 59(1): 159-169, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30422654

RESUMO

Recent research has increasingly suggested that the crucial factors affecting drug potencies are related not only to the thermodynamic properties but also to the kinetic properties. Therefore, in silico prediction of ligand-binding kinetic properties, especially the dissociation rate constant ( koff), has aroused more and more attention. However, there are still a lot of challenges that need to be addressed. In this paper, steered molecular dynamics (SMD) combined with residue-based energy decomposition was employed to predict the dissociation rate constants of 37 HIV-1 protease inhibitors (HIV-1 PIs). For the first time, a predictive model of the dissociation rate constant was established by using the interaction-energy fingerprints sampled along the ligand dissociation pathway. On the basis of the key fingerprints extracted it can be inferred that the dissociation rates of 37 HIV-1 PIs are basically determined in the first half of the dissociation processes and that the H-bond interactions with active-site Asp25 and van der Waals interactions with flap-region Ile47 and Ile50 have important influences on the dissociation processes. In general, the strategy established in this paper can provide an efficient way for the prediction of dissociation rate constants as well as the unbinding mechanism research.


Assuntos
Inibidores da Protease de HIV/química , Simulação de Dinâmica Molecular , Domínio Catalítico , Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacologia , Ligações de Hidrogênio , Cinética , Termodinâmica
8.
Eur J Med Chem ; 162: 194-202, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445267

RESUMO

A series of novel pleuromutilin derivatives embracing 7H-pyrrolo[2,3-d]pyrimidine moiety were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative pathogens as well as in vivo efficacy in lethal systemic infected mice. Most compounds displayed good in vitro potency against MSSA, MRSA, MSSE, MRSE and E. faecium (MIC = 0.0625-4 µg/mL), especially 15a, 15b and 15o showed excellent activity that even more active than the comparator valnemulin. The in vivo efficacy investigation exhibited compound 15a (ED50 = 16.0 mg/kg) had comparable activity to valnemulin (ED50 = 13.5 mg/kg). The results provided by the dose-response study demonstrated 15a can supply infected mice with 70% survival rate at dose of 40 mg/kg via intragastric (i.g.) administration.


Assuntos
Antibacterianos/farmacologia , Animais , Antibacterianos/síntese química , Infecções Bacterianas/tratamento farmacológico , Diterpenos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Relação Dose-Resposta a Droga , Camundongos , Compostos Policíclicos , Pirimidinas , Taxa de Sobrevida
9.
Sensors (Basel) ; 19(1)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30577675

RESUMO

Electronic skin is an important means through which robots can obtain external information. A novel flexible tactile sensor capable of simultaneously detecting the contact position and force was proposed in this paper. The tactile sensor had a three-layer structure. The upper layer was a specially designed conductive film based on indium-tin oxide polyethylene terephthalate (ITO-PET), which could be used for detecting contact position. The intermediate layer was a piezoresistive film used as the force-sensitive element. The lower layer was made of fully conductive material such as aluminum foil and was used only for signal output. In order to solve the inconsistencies and nonlinearity of the piezoresistive properties for large areas, a Radial Basis Function (RBF) neural network was used. This includes input, hidden, and output layers. The input layer has three nodes representing position coordinates, X, Y, and resistor, R. The output layer has one node representing force, F. A sensor sample was fabricated and experiments of contact position and force detection were performed on the sample. The results showed that the principal function of the tactile sensor was feasible. The sensor sample exhibited good consistency and linearity. The tactile sensor has only five lead wires and can provide the information support necessary for safe human-computer interactions.

10.
Sensors (Basel) ; 18(12)2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30558327

RESUMO

Tactility is an essential perception for intelligent equipment to acquire external information. It can improve safety and performance during human-machine interactions. Based on the uniqueness theorem of the electrostatic field, a novel flexible film tactile sensor that can detect contact position and be made into any plane shape is proposed in this paper. The tactile sensor included an indium tin oxide (ITO) film, which was uniformly coated on the polyethylene terephthalate (PET) substrate. A specially designed strong conductive line was arranged along the edge of the flexible ITO film, which has weak conductivity. A bias excitation was applied to both ends of the strong conductive line. Through the control of the shape of the strong conductive line, a uniform electric field can be constructed in the whole weak conductive plane. According to the linear relationship between position and potential in the uniform electric field, the coordinate of the contact position can be determined by obtaining the potential of the contact point in the weak conducting plane. The sensor uses a three-layer structure, including an upper conductive layer, an intermediate isolation layer, and a lower conductive layer. A tactile sensor sample was fabricated. The experiment results showed that the principle of the tactile sensor used for the contact position detection is feasible and has certain precision of position detection. The sensor has good flexibility, and can be made into any plane shape, and has only four wires. It is capable of covering large areas of robot arms, and provides safety solutions for most robots.

11.
Medchemcomm ; 9(11): 1961-1971, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568763

RESUMO

Toll-like receptors (TLRs) are important pattern recognition receptors to human innate immunity, which can recognize pathogen-associated molecular patterns and initiate innate immune responses. As the receptor of single stranded RNA (ssRNA), toll-like receptor 8 (TLR8) has potential in the treatment of tumors, microbial infection, and inflammatory diseases. Herein, an emerging chemical pattern (ECP) method was utilized to predict the key chemical patterns of TLR8 agonists. Based on the ECPs discovered, a robust and predictive ECP model was derived with prediction accuracies of 83.3%, 81.0%, and 80.0% for 132 training samples, 79 validation samples, and 75 test samples, respectively. When the ECP model was applied with a molecular docking method, the hit rate of TLR8 agonists was greatly enhanced. The results of ECP-based hierarchical cluster analysis and Connolly surface analysis of the TLR8 receptor showed that the H-bonding, hydrophilic and hydrophobic potentials as well as the unbalanced degree of property distributions are very important for distinguishing the TLR8 agonists from non-agonists.

12.
J Prosthet Dent ; 120(4): 609-616, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29724549

RESUMO

STATEMENT OF PROBLEM: The use of composite resin to restore teeth has increased substantially during the last decades. However, secondary caries and the fracture of restorations are the leading reasons for clinical restoration failure. Mechanically strong composite resins with caries-inhibition capabilities are needed. Although antibacterial dimethacrylate quaternary ammonium monomers have been synthesized, composite resin containing dimethacrylate quaternary ammonium monomers and glass fillers has rarely been reported. PURPOSE: The purpose of this in vitro study was to evaluate the possibility of the clinical use of an experimental composite resin containing urethane dimethacrylate quaternary ammonium compound (UDMQA-12) by investigating its antibacterial activity, cytotoxicity, flexural strength, and flexural modulus. MATERIAL AND METHODS: Antibacterial activity against Streptococcus mutans was investigated by means of direct contact test. The antibacterial activity of specimens after water immersion and saliva treatment was also tested. These were compared with a commercially available composite resin, Z250, and a glass ionomer cement, Fuji VII. Effects of the eluent from the experimental composite resin on the metabolic activity of human dental pulp cells were quantified. Disks of 1 mm in thickness and 15 mm in diameter were used in the antibacterial and cytotoxic tests. Flexural strength and flexural modulus were measured with a 3-point bend test with bars of 2×2×25 mm. Three commercially available composite resins (Filtek Z250, G-aenial Anterior, and G-aenial Posterior) were used as controls in the flexural test. RESULTS: Bacterial growth was inhibited on the experimental composite resin. After water immersion or saliva treatment, the experimental composite resin showed significant antibacterial effect compared with the conventional composite resin (P<.05). No significant difference was found in cytotoxicity between the experimental composite resin and the conventional composite resin (P>.05), and a significantly higher cytotoxicity was shown by glass ionomer cement compared with the experimental composite resin and the conventional composite resin (P<.05). The conventional composite resin had the highest flexural strength and flexural modulus (P<.05), followed by the experimental composite resin, then G-ænial Posterior and G-ænial Anterior. CONCLUSIONS: The antibacterial experimental composite resin was biocompatible and had mechanical properties similar to those of some commercially available composite resins. It might, therefore, be useful in preventing the occurrence of secondary caries.


Assuntos
Antibacterianos/farmacologia , Resinas Compostas/farmacologia , Citotoxinas/farmacologia , Compostos de Amônio Quaternário/farmacologia , Antibacterianos/química , Resinas Compostas/química , Citotoxinas/química , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Resistência à Flexão , Humanos , Técnicas In Vitro , Metacrilatos/química , Metacrilatos/farmacologia , Testes de Sensibilidade Microbiana , Poliuretanos/química , Poliuretanos/farmacologia , Compostos de Amônio Quaternário/química , Streptococcus mutans/efeitos dos fármacos
13.
Cell Death Dis ; 9(2): 229, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29445104

RESUMO

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR2-overexpressing MSCs (MSCsCXCR2) for mucositis treatment. Indeed, MSCsCXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSCCXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.


Assuntos
Quimiocina CXCL2/genética , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Úlceras Orais/terapia , Receptores de Interleucina-8B/genética , Estomatite/terapia , Ácido Acético , Animais , Quimiocina CXCL2/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Raios gama , Expressão Gênica , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Úlceras Orais/etiologia , Úlceras Orais/genética , Úlceras Orais/patologia , Cultura Primária de Células , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Estomatite/etiologia , Estomatite/genética , Estomatite/patologia , Língua/efeitos dos fármacos , Língua/metabolismo , Língua/patologia , Língua/efeitos da radiação , Transgenes
14.
Inflammation ; 41(2): 409-417, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29178062

RESUMO

The AIM2 inflammasome pathway has been determined to play an important role in cellular immune defense against bacterial and viral infections; however, its function and regulatory mechanism in human dental pulp cells (HDPCs) during pulpitis remains poorly understood. In this study, we explored whether the AIM2 inflammasome pathway was activated in HDPCs in response to dsDNA and defined its role in regulating IL-1ß secretion. We demonstrated that stimulation with IFN-γ and cytoplasmic DNA significantly activated the AIM2 inflammasome and increased IL-1ß secretion in HDPCs. Moreover, AIM2 overexpression significantly up-regulated both cleaved Caspase-1 expression and IL-1ß release in HDPCs, while suppression of ASC and Caspase-1 resulted in down-regulation of cleaved Caspase-1 and IL-1ß secretion. These results suggest that Caspase-1-dependent IL-1ß processing and secretion require the AIM2 inflammasome pathway in HDPCs and that the AIM2 inflammasome pathway is critical for regulation of the dental pulp immune response.


Assuntos
Proteínas de Ligação a DNA/metabolismo , DNA/fisiologia , Polpa Dentária/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Caspase 1 , Células Cultivadas , Proteínas de Ligação a DNA/fisiologia , Polpa Dentária/citologia , Polpa Dentária/imunologia , Humanos , Inflamassomos/fisiologia , Pulpite
15.
Exp Ther Med ; 14(1): 73-78, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28672895

RESUMO

Pulp capping is a restorative technique employed in an attempt to maintain pulpal vitality and generate reparative dentin. Ca2+ released from capping materials is suggested to promote reparative dentin formation. Transient receptor potential channel 6 (TRPC6) is a receptor-operated Ca2+ channel that serves an important role in Ca2+ influx in the majority of non-excitable cells, and influences the calcium signaling and cell respond. Therefore, the purpose of the present study was to gain an insight into the role of TRPC6 in the odontoblastic differentiation of human dental pulp cells (HDPCs). Human dental pulp tissues and HDPCs were obtained from healthy third molars. By immunohistochemical staining, TRPC6 was observed to be highly expressed in the dental pulp tissue, particularly in the odontoblast layer. In addition, the protein level of TRPC6 was increased in a time-dependent manner during odontogenic differentiation of HDPCs. Downregulation of TRPC6 by a lentivirus vector containing TRPC6 shRNA inhibited the process of odontogenic differentiation in HDPCs. In conclusion, the current data demonstrated that TRPC6 served a significant role in the odontogenic differentiation of HDPCs, suggesting it may be a promising therapeutic target in regenerative endodontics.

16.
J Endod ; 43(2): 315-320, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28041683

RESUMO

INTRODUCTION: Calcium ions (Ca2+) actively participate in reparative dentin formation by promoting cellular proliferation and differentiation of human dental pulp cells (hDPCs). Transient receptor potential cation channel, subfamily C, member 1 (TRPC1) activates Ca2+ entry upon store depletion in a variety of cell types. However, the function of TRPC1 in hDPCs has not been reported. Therefore, we aimed to analyze the role of TRPC1 in hDPCs undergoing odontoblast-like differentiation. METHODS: Immunohistochemical staining was used to determine the distribution of TRPC1 in pulp tissues. Western blot analysis was used to detect the protein level of TRPC1 in the odontoblast-like differentiation of hDPCs. Knockdown of TRPC1 was performed with an adenoviral vector to evaluate the role of TRPC1 in hDPCs during odontoblast-like differentiation. RESULTS: The results showed that TRPC1 was highly expressed in the cytoplasm of dental pulp cells, especially in the odontoblast layer of the healthy pulp. Moreover, the protein level of TRPC1 increased in a time-dependent manner during the odontoblast-like differentiation of hDPCs. Importantly, knockdown of TRPC1 attenuated the process of odontoblast-like differentiation as indicated by the reduction in mineralized nodules and the down-regulation of dentin sialophosphoprotein and dentin matrix protein 1. Moreover, knockdown of TRPC1 decreased Ca2+ entry to the cytoplasm of hDPCs. CONCLUSIONS: Our data indicated a pivotal role of TRPC1 in the odontoblastlike differentiation of hDPCs, which may be a therapeutic target to enhance reparative dentin formation.


Assuntos
Diferenciação Celular/fisiologia , Polpa Dentária/citologia , Odontoblastos/fisiologia , Canais de Cátion TRPC/fisiologia , Adolescente , Adulto , Western Blotting , Cálcio/metabolismo , Células Cultivadas , Polpa Dentária/fisiologia , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
17.
Integr Biol (Camb) ; 8(11): 1158-1169, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27731447

RESUMO

ATP-binding cassette (ABC) exporters mediate vital transport of a variety of molecules across the lipid bilayer in all organisms. To explore the allosteric effect of ATP binding at the asymmetric ATPase sites, molecular dynamics simulations were performed on the nucleotide-binding domains (NBDs) of a heterodimeric exporter TM287/288 in 4 different ATP-bound states. The results showed that ATP bound at the degenerate site can maintain a semi-open conformation of NBD1-NBD2, which may be defective in ATP hydrolysis. By contrast, when bound at the consensus site, ATP can induce an intra-domain rotation of the α-helical subdomain towards the RecA-like subdomain of NBD2 at the degenerate site. The rotation of the α-helical subdomain rearranged the hydrogen bond networks at the NBD1-NBD2 interface, induced a significant conformational change in the D-loop at the degenerate site and inter- and intra-domain communications at both sites, and eventually elicited dimerization of NBD1-NBD2. These findings indicate that the asymmetric ATPase sites of the heterodimeric exporter are structurally and functionally distinct.


Assuntos
Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/ultraestrutura , Adenosina Trifosfatases/química , Adenosina Trifosfatases/ultraestrutura , Trifosfato de Adenosina/química , Simulação de Dinâmica Molecular , Regulação Alostérica , Dimerização , Modelos Químicos , Ligação Proteica , Conformação Proteica , Domínios Proteicos
18.
J Chem Inf Model ; 56(10): 2061-2068, 2016 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-27624663

RESUMO

Accumulated evidence suggests that the in vivo biological potency of a ligand is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of the protein-ligand interaction (PLI). However, the existing experimental and computational techniques are largely insufficient and limited in large-scale measurements or accurate predictions of the kinetic properties of PLI. In this work, elaborate efforts have been made to develop interconsistent, reasonable, and predictive models of the association rate constant (kon), dissociation rate constant (koff), and equilibrium dissociation constant (KD) of a series of HIV protease inhibitors with different structural skeletons. The results showed that nine Volsurf descriptors derived from water (OH2) and hydrophobic (DRY) probes are key molecular determinants for the kinetic and thermodynamic properties of HIV-1 protease inhibitors. To the best of our knowledge, this is the first time that interconsistent and reasonable models with strong prediction power have been established for both the kinetic and thermodynamic properties of HIV protease inhibitors.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/enzimologia , Desenho de Drogas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Cinética , Modelos Moleculares , Termodinâmica
19.
Int J Pharm ; 502(1-2): 61-9, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-26899974

RESUMO

P-glycoprotein (P-gp), an ATP-binding cassette (ABC) multidrug transporter, can actively transport a broad spectrum of chemically diverse substrates out of cells and is heavily involved in multidrug resistance (MDR) in tumors. So far, the multiple specific binding sites remain a major obstacle in developing an efficient prediction method for P-gp substrates. Herein, emerging chemical pattern (ECP) combined by hierarchical cluster analysis was utilized to predict P-gp substrates as well as their potential binding sites. An optimal ECP model using only 3 descriptors was established with prediction accuracies of 0.80, 0.81 and 0.74 for 803 training samples, 120 test samples, and 179 independent validation samples, respectively. Hierarchical cluster analysis (HCA) of the ECPs of P-gp substrates derived 2 distinct ECP groups (ECPGs). Interestingly, HCA of the P-gp substrates based on ECP similarities also showed 2 distinct classes, which happened to be dominated by the 2 ECPGs, respectively. In the light of available experimental proofs and molecular docking results, the 2 distinct ECPGs were proved to be closely related to the binding profiles of R- and H-site substrates, respectively. The present study demonstrates, for the first time, a successful ECP model, which can not only accurately predict P-gp substrates, but also identify their potential substrate-binding sites.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Modelos Moleculares , Sítios de Ligação , Análise por Conglomerados , Preparações Farmacêuticas/metabolismo
20.
Cell Tissue Res ; 364(2): 309-18, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26646542

RESUMO

Long noncoding RNAs (lncRNAs) have recently emerged as an important class of regulatory molecules in diverse biological processes, although lncRNA involvement in the odontoblast-like differentiation of human dental pulp cells (hDPCs) is poorly understood. We investigate the expression of lncRNAs in this differentiation and explore their underlying role and the involved mechanism. Integrated comparative lncRNA microarray profiling was used to examine lncRNA expression during this differentiation. The differential expression of lncRNAs was validated by quantitative real-time reverse transcription plus the polymerase chain reaction. Differential lncRNA overexpression was performed with an adenoviral vector and the role and mechanism was then investigated in odontoblast-like differentiation. We identified 139 differentially expressed lncRNAs during this differentiation. Among them, five lncRNAs differentially expressed in microarray analysis were validated. Notably, lncRNA DANCR expression was significantly downregulated during hDPC differentiation to odontoblast-like cells in a time-dependent manner. Moreover, lncRNA DANCR overexpression blocked mineralized nodule formation and the expression of DSPP and DMP-1 in hDPCs after 14 days of odontogenic induction. Importantly, the upregulation of DANCR significantly decreased the expression levels of p-GSK-3ß and ß-catenin expression indicating that lncRNA DANCR can inhibit the activation of the Wnt/ß-catenin signal pathway during the odontoblast-like differentiation of hDPCs. Thus, the modulation of Wnt/ß-catenin signaling by lncRNA DANCR represents a potential therapeutic option for reparative dentin formation and regenerative endodontics.


Assuntos
Diferenciação Celular/genética , Polpa Dentária/citologia , Odontoblastos/citologia , Odontogênese/genética , RNA Longo não Codificante/genética , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/genética , beta Catenina/antagonistas & inibidores , Células Cultivadas , Dentina/metabolismo , Glicogênio Sintase Quinase 3 beta/biossíntese , Humanos , beta Catenina/biossíntese
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