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1.
ACS Chem Neurosci ; 11(5): 772-782, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32023408

RESUMO

Conformational transition from the normal cellular form of prion protein (PrPC) to the pathogenic "scrapie" form (PrPSc) is considered to be a key event in the occurrence of prion disease. Additionally, the H2 C-terminus is widely considered to be a vital site for PrP conformational transition, which can be used as an important region to explore the potential mechanism of PrP misfolding. Therefore, to study the misfolding mechanism of PrP, 500 ns well-tempered metadynamics simulations were performed by focusing on the H2 C-terminus of PrP. For comparison, three systems were designed in total, including PrP in neutral and acidic conditions, as well as H187R mutant. The resulting free energy surfaces (FESs) obtained from metadynamics simulations reveal that acidic conditions and H187R mutation can facilitate PrP misfolding by decreasing free energy barriers for conformational transition and forming energy stable conformational states. Further analyses aimed at H2 C-terminus show that due to the increase of positive charge on residue 187 in both acidic and H187R systems, the electrostatic repulsion of residue 187 and R136/R156 increases greatly, which disrupts the electrostatic interaction network around H2 C-terminus and exposes the hydrophobic core to the solvent. Taken together, acidic conditions and H187R mutation can accelerate PrP misfolding mainly by forming more energetically stable metastable conformations with lower free energy barriers, and electrostatic network disruption involving residue 187 drives the initial misfolding of H2 C-terminus. This study provides quantitative insight into the related function of the H2 C-terminus in the PrP misfolding process, which may guide H2 C-terminus mediated drug design in the future.

2.
Environ Health Perspect ; 128(2): 27002, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32074470

RESUMO

BACKGROUND: Endocrine disrupting chemicals (EDCs) are xenobiotics that mimic the interaction of natural hormones and alter synthesis, transport, or metabolic pathways. The prospect of EDCs causing adverse health effects in humans and wildlife has led to the development of scientific and regulatory approaches for evaluating bioactivity. This need is being addressed using high-throughput screening (HTS) in vitro approaches and computational modeling. OBJECTIVES: In support of the Endocrine Disruptor Screening Program, the U.S. Environmental Protection Agency (EPA) led two worldwide consortiums to virtually screen chemicals for their potential estrogenic and androgenic activities. Here, we describe the Collaborative Modeling Project for Androgen Receptor Activity (CoMPARA) efforts, which follows the steps of the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP). METHODS: The CoMPARA list of screened chemicals built on CERAPP's list of 32,464 chemicals to include additional chemicals of interest, as well as simulated ToxCast™ metabolites, totaling 55,450 chemical structures. Computational toxicology scientists from 25 international groups contributed 91 predictive models for binding, agonist, and antagonist activity predictions. Models were underpinned by a common training set of 1,746 chemicals compiled from a combined data set of 11 ToxCast™/Tox21 HTS in vitro assays. RESULTS: The resulting models were evaluated using curated literature data extracted from different sources. To overcome the limitations of single-model approaches, CoMPARA predictions were combined into consensus models that provided averaged predictive accuracy of approximately 80% for the evaluation set. DISCUSSION: The strengths and limitations of the consensus predictions were discussed with example chemicals; then, the models were implemented into the free and open-source OPERA application to enable screening of new chemicals with a defined applicability domain and accuracy assessment. This implementation was used to screen the entire EPA DSSTox database of ∼875,000 chemicals, and their predicted AR activities have been made available on the EPA CompTox Chemicals dashboard and National Toxicology Program's Integrated Chemical Environment. https://doi.org/10.1289/EHP5580.

3.
ACS Chem Neurosci ; 11(4): 628-637, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31968162

RESUMO

CC chemokine receptor 2 (CCR2) and its endogenous CC chemokine ligands are associated with numerous inflammatory, neurodegenerative diseases, and cancer. CCR2 is becoming an attractive target in the treatment of autoimmune disease and neurodegenerative diseases. The orthosteric antagonist BMS-681 and allosteric antagonist CCR2-RA-[R] of CCR2 show positive binding cooperativity. We performed well-tempered metadynamics simulations and Gaussian accelerated MD simulations to reveal the influence of the orthosteric antagonist on the unbinding of allosteric antagonist of CCR2. We revealed different unbinding pathways of CCR2-RA-[R] in binary complex CCR2-VT5 and ternary complex CCR2-73R-VT5. The different unbinding pathways of CCR2-RA-[R] are due to the conformational dynamics of TM6. We obtained the significant conformational differences of the intracellular side of TM6 upon CCR2 binding to different ligands by GaMD simulation. The conformational dynamics of TM6 are consistent with the unbinding pathway analysis. GaMD simulations indicate that BMS-681 binding restricts the bend of intracellular side of TM6 by stabilizing the extracellular sides of TM6 and TM7. The charged residues Arg2065.43 of TM5 and Glu2917.39 of TM7 play key roles in stabling TM7 and TM6. TM6 and TM7 are crucial components in the orthosteric and allosteric binding sites. Our results illustrate the conformational details about the effect of the orthosteric antagonist on the allosteric antagonist of CCR2. The conformational dynamics of CCR2 upon binding to different ligands can provide a rational basis for development of allosteric ligands of CCR2.

4.
Phys Chem Chem Phys ; 21(45): 25276-25289, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31701109

RESUMO

As a member of the bromodomain and extra terminal domain (BET) protein family, bromodomain-containing protein 4 (BRD4) is an epigenetic reader and can recognize acetylated lysine residues in histones. BRD4 has been regarded as an essential drug target for cancers, inflammatory diseases and acute heart failure, and therefore the discovery of potent BRD4 inhibitors with novel scaffolds is highly desirable. In this study, the crystalline water molecules in BRD4 involved in ligand binding were analyzed first, and the simulation results suggest that several conserved crystalline water molecules are quite essential to keep the stability of the crystalline water network and therefore they need to be reserved in structure-based drug design. Then, a docking-based virtual screening workflow with the consideration of the conserved crystalline water network in the binding pocket was utilized to identify the potential inhibitors of BRD4. The in vitro fluorescence resonance energy transfer (HTRF) binding assay illustrates that 4 hits have good inhibitory activity against BRD4 in the micromolar regime, including three compounds with IC50 values below 5 µM and one below 1 µM (0.37 µM). The structural analysis demonstrates that three active compounds possess novel scaffolds. Moreover, the interaction patterns between the hits and BRD4 were characterized by molecular dynamics simulations and binding free energy calculations, and then several suggestions for the further optimization of these hits were proposed.


Assuntos
Simulação de Acoplamento Molecular , Proteínas Nucleares/química , Fatores de Transcrição/química , Água/química , Proteínas de Ciclo Celular , Cristalização , Transferência Ressonante de Energia de Fluorescência , Humanos , Simulação de Dinâmica Molecular , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores
5.
Front Chem ; 7: 764, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781546

RESUMO

Recently, small-molecule compounds have been reported to block the PD-1/PD-L1 interaction by inducing the dimerization of PD-L1. All these inhibitors had a common scaffold and interacted with the cavity formed by two PD-L1 monomers. This special interactive mode provided clues for the structure-based drug design, however, also showed limitations for the discovery of small-molecule inhibitors with new scaffolds. In this study, we revealed the structure-activity relationship of the current small-molecule inhibitors targeting dimerization of PD-L1 by predicting their binding and unbinding mechanism via conventional molecular dynamics and metadynamics simulation. During the binding process, the representative inhibitors (BMS-8 and BMS-1166) tended to have a more stable binding mode with one PD-L1 monomer than the other and the small-molecule inducing PD-L1 dimerization was further stabilized by the non-polar interaction of Ile54, Tyr56, Met115, Ala121, and Tyr123 on both monomers and the water bridges involved in ALys124. The unbinding process prediction showed that the PD-L1 dimerization kept stable upon the dissociation of ligands. It's indicated that the formation and stability of the small-molecule inducing PD-L1 dimerization was the key factor for the inhibitory activities of these ligands. The contact analysis, R-group based quantitative structure-activity relationship (QSAR) analysis and molecular docking further suggested that each attachment point on the core scaffold of ligands had a specific preference for pharmacophore elements when improving the inhibitory activities by structural modifications. Taken together, the results in this study could guide the structural optimization and the further discovery of novel small-molecule inhibitors targeting PD-L1.

6.
ACS Chem Neurosci ; 10(12): 4810-4823, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31661961

RESUMO

The microtubule-associated protein tau is critical for the development and maintenance of the nervous system. Tau dysfunction is associated with a variety of neurodegenerative diseases called tauopathies, which are characterized by neurofibrillary tangles formed by abnormally aggregated tau protein. Studying the aggregation mechanism of tau protein is of great significance for elucidating the etiology of tauopathies. The hexapeptide 306VQIVYK311 (PHF6) of R3 has been shown to play a vital role in promoting tau aggregation. In this study, long-term all-atom molecular dynamics simulations in explicit solvent were performed to investigate the mechanisms of spontaneous aggregation and template-induced misfolding of PHF6, and the dimerization at the early stage of nucleation was further specifically analyzed by the Markov state model (MSM). Our results show that PHF6 can spontaneously aggregate to form multimers enriched with ß-sheet structure and the ß-sheets in multimers prefer to exist in a parallel way. It is observed that PHF6 monomer can be induced to form a ß-sheet structure on either side of the template but in a different way. In detail, the ß-sheet structure is easier to form on the left side but does not extend well, but on the right side, the monomer can form the extended ß-sheet structure. Furthermore, MSM analysis shows that the formation of dimer mainly occurs in three steps. First, the separated monomers collide with each other at random orientations, and then a dimer with short ß-sheet structure at the N-terminal forms; finally, ß-sheets elongate to form an extended parallel ß-sheet dimer. During these processes, multiple intermediate states are identified and multiple paths can form a parallel ß-sheet dimer from the disordered coil structure. Moreover, the residues I308, V309, and Y310 play an essential role in the dimerization. In a word, our results uncover the aggregation and misfolding mechanism of PHF6 from the atomic level, which can provide useful theoretical guidance for rational design of effective therapeutic drugs against tauopathies.

7.
Mol Inform ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294911

RESUMO

Imidacloprid (IMI) is the first widely used neonicotinoid insecticide due to its high insecticidal activity and low toxicity. However, as its extensive use in crop protection, many insects are resistant to IMI. One of the main resistance mechanisms of insects to IMI is Y151-S and R81T mutations in nicotinic acetylcholine receptor (nAChR). However, how these two mutations affect the interaction of IMI with nAChR is unknown. Here, to uncover the resistant mechanism of nAChR to IMI due to Y151-S and R81T mutations, molecular dynamics simulations and molecular mechanics/generalized Born surface area (MM-GBSA) calculation, residue interaction network (RIN) analysis were performed. Due that the structure of nAChR is still unkonwn, the crystal structure of lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) was used here to simulate nAChR. Y151 and R81 in nAChR correspond to H145 and Q55 in Ls-AChBP, respectively. The calculated binding free energy indicated that two mutations reduced the binding ability of IMI with Ls-AChBP. Q55T mutation reduced the contribution of several key residues, such as W53, T55, Y113, T144 and C187. As for H145-S mutation, the contribution of W53, Q55 and Y113 residues also decreased. RIN analysis showed that two mutants changed the binding pocket by changing the conformation of residues that interact directly with the mutated residues. The obtained resistance mechanism of IMI will be helpful for the design of potent insecticides.

8.
Front Chem ; 7: 385, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214568

RESUMO

The antioxidant response elements (AREs) play a significant role in occurrence of oxidative stress and may cause multitudinous toxicity effects in the pathogenesis of a variety of diseases. Determining if one compound can activate AREs is crucial for the assessment of potential risk of compound. Here, a series of predictive models by applying multiple deep learning algorithms including deep neural networks (DNN), convolution neural networks (CNN), recurrent neural networks (RNN), and highway networks (HN) were constructed and validated based on Tox21 challenge dataset and applied to predict whether the compounds are the activators or inactivators of AREs. The built models were evaluated by various of statistical parameters, such as sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC) and receiver operating characteristic (ROC) curve. The DNN prediction model based on fingerprint features has best prediction ability, with accuracy of 0.992, 0.914, and 0.917 for the training set, test set, and validation set, respectively. Consequently, these robust models can be adopted to predict the ARE response of molecules fast and accurately, which is of great significance for the evaluation of safety of compounds in the process of drug discovery and development.

9.
Front Chem ; 7: 406, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214579

RESUMO

The smoothened receptor (Smo) plays a key role in Hedgehog (Hh) signaling pathway and it has been regarded as an efficacious therapeutic target for basal cell carcinoma (BCC) and medulloblastoma (MB). Nevertheless, the resistance mutation and active mutants of Smo have put forward the requirement of finding more effective inhibitors. Herein, we performed metadynamics simulations on Smo bound with vismodegib (Smo-Vismod) and with cholesterol (Smo-CLR), respectively, to explore the inhibition mechanism of vismodegib. The simulation results indicated that vismodegib-induced shifts of TM5, TM6, and TM7, which permitted the extracellular extension of TM6 and extracellular loop3 (ECL3) to enter the extracellular cysteine-rich domain (CRD) groove. Therefore, an open CRD groove that has not been noticed previously was observed in Smo-Vismod complex. As a consequence, the occupied CRD groove prevents the binding of cholesterol. In addition, the HD and ECLs play crucial roles in the interaction of CRD and TMD. These results reveal that TM5, TM6, and TM7 play important roles in allosteric inhibition the activation of Smo and disrupting cholesterol binding by vismodegib binding. Our results are expected to contribute to understanding the allosteric inhibition mechanism of Smo by vismodegib. Moreover, the detailed conformational changes contribute to the development of novel Smo inhibitors against resistance mutation and active mutants of Smo.

10.
ACS Chem Neurosci ; 10(6): 2718-2729, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31070897

RESUMO

The conformational transition of prion protein (PrP) from a native form PrPC to a pathological isoform PrPSc is the main cause of a number of prion diseases in human and animals. Thus, understanding the molecular basis of conformational transition of PrP will be valuable for unveiling the etiology of PrP-related diseases. Here, to explore the potential misfolding mechanism of PrP under the acidic condition, which is known to promote PrP misfolding and trigger its aggregation, the conventional and accelerated molecular dynamics (MD) simulations combined with the Markov state model (MSM) analysis were performed. The conventional MD simulations reveal that, at an acidic pH, the globular domain of PrP is partially unfolded, particularly for the α2 C-terminus. Structural analysis of the key macrostates obtained by MSM indicates that the α2 C-terminus and the ß2-α2 loop may serve as important sites for the pH-induced PrP misfolding. Meanwhile, the α1 may also participate in the pH-induced structural conversion by moving away from the α2-α3 subdomain. Notably, dynamical network analysis of the key metastable states indicates that the protonated H187 weakens the interactions between the α2 C-terminus, α1-ß2 loop, and α2-α3 loop, leading these domains, especially the α2 C-terminus, to become unstable and to begin to misfold. Therefore, the α2 C-terminus plays a key role in the PrP misfolding process and serves as a potential site for drug targeting. Overall, our findings can deepen the understanding of the pathogenesis related to PrP and provide useful guidance for the future drug discovery.

11.
Eur J Pharmacol ; 849: 43-49, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30707959

RESUMO

Colorectal cancer (CRC) is a common malignancy and the leading cause of cancer death worldwide. According to previous studies, vanillin possesses pharmacological and anticancer activities. In this work, we have modified the structure of vanillin to obtain a vanillin derivative called 4-(1H-imidazo [4,5-f][1,10]-phenanthrolin-2-yl)-2-methoxyphenol (IPM711), which has improved anticancer activity. The present study is intended to explore the anti-colorectal cancer activity of IPM711 in HT29 and HCT116 cells. The results of this study suggest that IPM711 can inhibit the growth, invasion and migration of HT29 and HCT116 cells. Western blot and molecular docking showed that IPM711 could bind to a Wnt/ß-catenin signaling receptor to inhibit cell growth, invasion and migration in HT29 cells. Based on these results, IPM711 is a promising anticancer drug candidate for human colorectal cancer therapy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzaldeídos/química , Benzaldeídos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/metabolismo , Benzaldeídos/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores Frizzled/química , Receptores Frizzled/metabolismo , Células HCT116 , Células HT29 , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica
12.
ACS Chem Neurosci ; 10(3): 1854-1865, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30665304

RESUMO

The level of tau aggregation into neurofibrillary tangles, including paired helical filament (PHF) and straight filament (SF), is closely associated with Alzheimer's disease. Despite the pathological importance of misfolding and aggregation of tau, the corresponding mechanism remains unclear. Therefore, to uncover the misfolding mechanism of the tau monomer upon induction of formed PHF and SF, in this study, a conventional molecular dynamics simulation combined with a steered molecular dynamics simulation was performed to study the dissociation of the boundary chain. Interestingly, our results show that the dissociation mechanisms of the boundary chain in PHF and SF are different. In PHF, the boundary chain begins to dissociate from regions ß2 and ß3 and ends at ß8. However, in SF, it is simultaneously dissociated from ß1 and ß8 and ends at ß5. The dissociation of the boundary chain is the reverse of template-induced misfolding of the monomer. Therefore, we can deduce the misfolding mechanism of the monomer upon induction of the template. For PHF, ß8 first interacts with the template by hydrophobic interaction. Then ß7, ß6, ß5, ß4, and ß1 sequentially bind to the template by electrostatic and hydrophobic interactions. After ß1 binds to the template, ß2 and ß3 very quickly bind to the template through hydrophobic interaction. For SF, ß5 of the monomer first interacts with the template by electrostatic attraction. Then ß4 and ß6, ß3 and ß7, and ß2 and ß8 bind to the template in turn. Finally, ß1 and ß8 are fully bound to the template by hydrophobic interaction. The obtained results will be vital for understanding the earlier events during misfolding and aggregation of tau.

13.
Environ Res ; 171: 1-10, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30641367

RESUMO

As the broad application of graphene in the biomedical field, it is urgent and important to evaluate how the graphene affects the structure and function of the proteins in our body, especially the amyloid-related proteins. Prion protein, as a typical amyloid protein, it misfolding and aggregation will lead to serious prion diseases. To explore if graphene promotes or inhibits the formation of amyloid, here, we combined the experimental and molecular dynamics (MD) simulation methods to study the influence of graphene on the globular domain of prion protein (PrP117-231). The results from fluorescence quenching and circular dichroism spectrum showed that the addition of graphene changed the secondary structure of prion protein largely, mainly reflecting in the reduced α-helix structure and the increased coil structure, indicating graphene may strengthen the misfolding inclination of prion. To further uncover the mechanism of conformational change of prion under the induction of graphene, the all-atoms MD simulations in explicit solvent were performed. Our simulations suggest that prion protein can be quickly and tightly adsorbed onto graphene together with the weak conformational rearrangement and may reorient when approaching the surface. The Van der Waals' force drive the adsorption process. In the induction of graphene, H1 and S2-H2 loop regions of prion become unstable and prion begins to misfold partially. Our work shows that graphene can induce the misfolding of prion protein and may cause the potential risk to biosystems.


Assuntos
Grafite/química , Proteínas Priônicas/química , Humanos , Simulação de Dinâmica Molecular , Príons , Estrutura Secundária de Proteína
14.
ACS Chem Neurosci ; 10(3): 1575-1584, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30372027

RESUMO

The opioid receptors belong to the class A seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). The κ-opioid receptor (KOR) is a subfamily of four opioid receptors. The endogenous peptide and a variety of selective agonists and antagonists of KOR have been developed. The structurally similar ligands at the same site cause completely opposite biological functions and induce different conformational changes. To shed light on the conformation ensembles and conformational dynamics in activation and deactivation processes of KOR, we performed all-atom, long-time Gaussian accelerated molecular dynamics simulation (GaMD) on KOR binding with agonist epoxymorphinan MP1104 and antagonist JDTic, respectively. Our results revealed different conformation ensembles of KOR binding with agonist and with antagonist. Agonist binding stabilizes the active state of key motifs including DYYNM motif and CWxP motif, and biases the conformation equilibria toward the active state. Antagonist binding will not destroy inactive conformation equilibria, by keeping the stable inactive state of these crucial motifs. We found that the inactive apo form of KOR is the most stable state, while the active apo form relaxes readily to inactive state. Our results also revealed a stable intermediate (I), which is attributed to the hydrophobic interactions between Tyr2465.58 and TM6, as well as the steric hindrance of them. Our results not only show the conformation equilibria bias of KOR by binding with agonist and antagonist, but also provide the structural information for the design and discovery of potential ligands with different functions.

15.
J Chem Inf Model ; 59(1): 597-604, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30525607

RESUMO

Allosteric modulators, by targeting the less-conserved allosteric sites, represent an innovative strategy in drug discovery. These modulators have a distinctive advantage over orthosteric ligands that attach to the conserved, functional orthosteric sites. However, in structure-based drug design, it remains unclear whether allosteric protein structures determined without orthosteric ligand binding are suitable for allosteric drug screening. In this study, we performed large-scale conformational samplings of six representative allosteric proteins uncomplexed ( apo) and complexed ( holo) with orthosteric ligands to explore the effect of orthosteric site binding on the conformational dynamics of allosteric sites. The results, coupled with the redocking evaluation of allosteric modulators to their apo and holo proteins using their MD trajectories, indicated that orthosteric site binding had an effect on the dynamics of the allosteric sites and allosteric modulators preferentially bound to their holo proteins. According to the analysis data, we constructed a new correlation model for quantifying the allosteric site change driven by substrate binding to the orthosteric site. These results highlight the strong demand to select holo allosteric proteins as initial inputs in structure-based allosteric drug screening when the distance between orthosteric and allosteric sites in the protein is below 5 Å, which is expected to contribute to allosteric drug discovery.


Assuntos
Apoproteínas/química , Apoproteínas/metabolismo , Descoberta de Drogas/métodos , Simulação de Dinâmica Molecular , Sítio Alostérico/efeitos dos fármacos , Humanos , Conformação Proteica
16.
Chem Biol Drug Des ; 93(4): 628-637, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30566277

RESUMO

The interactions of complement receptor 2 (CR2) and the degradation fragment C3d of complement component C3 mediate the innate and adaptive immune systems. Due to the importance of C3d-CR2 interaction in the design of vaccines, many studies have indicated the interactions are pH-dependent. Moreover, C3d-CR2 interactions at pH 5.0 are unknown. To investigate the molecular mechanism of pH-regulating C3d-CR2 interaction, molecular dynamics simulations for C3d-CR2 complex in different pH are performed. Our results revealed that the protonation of His9 in C3d at pH 6.0 slightly weakens C3d-CR2 association as reducing pH from 7.4 to 6.0, initiated from a key hydrogen bond formed between Gly270 and His9 in C3d at pH 6.0. When reducing pH from 6.0 to 5.0, the protonation of His33 in C3d weakens C3d-SCR1 association by changing the hydrogen-bond network of Asp36, Glu37, and Glu39 in C3d with Arg13 in CR2. In addition, the protonation of His90 significantly enhances C3d-SCR2 association. This is because the enhanced hydrogen-bond interactions of His90 with Glu63 and Ser69 of the linker change the conformations of the linker, Cys112-Asn116 and Pro87-Gly91 regions. This study uncovers the molecular mechanism of the mediation of pH on C3d-CR2 interaction, which is valuable for vaccine design.


Assuntos
Complemento C3d/metabolismo , Simulação de Dinâmica Molecular , Receptores de Complemento 3d/metabolismo , Sítios de Ligação , Complemento C3d/química , Humanos , Concentração de Íons de Hidrogênio , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Complemento 3d/química , Termodinâmica
17.
J Chem Inf Model ; 59(5): 1909-1918, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30575391

RESUMO

The specific properties of carbon nanoparticles (NPs) have attracted great attention in applications in biotechnology and biomedicine, e.g., in the field of amyloidosis. To date, it is still indefinable whether carbon NPs would promote or inhibit the fibril formation of amyloid proteins. Here, to uncover the effects of carbon nanoparticles (NPs) including graphene and carbon nanotubes on the aggregation of prion proteins, whose misfolding and aggregation will lead to prion diseases, a ThT fluorescence assay and a molecular dynamics (MD) simulation were performed. The ThT fluorescence assay reveals that both graphene and carbon nanotubes can inhibit the fibril formation of prion proteins, especially graphene. Further MD simulation of the PrP127-147 tetramer with or without carbon NPs suggests that the interactions between prion proteins and carbon NPs reduce the aggregation tendency of PrP127-147 by decreasing the interpeptide interactions and thus inhibiting ß-sheet formation. Meanwhile, aromatic residues greatly contribute to the inhibition effects of carbon NPs by a π-π stacking interaction. The obtained results can increase our understanding on the interaction between nanoparticles and amyloid-related proteins.

18.
Colloids Surf B Biointerfaces ; 171: 451-460, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30075421

RESUMO

The ability to obtain a large number of human pluripotent stem cells (hPSCs) under chemically defined conditions plays a key role in clinical application of hPSCs. Chemically defined, economical and effective synthetic peptide displaying surfaces should be the optimal choice for clinical applications involving hPSCs. However, synthetic peptide displaying surfaces are worse than Matrigel surface in supporting cell adhesion and self-renewal. Moreover, the correlations between peptide amino acid sequences and the ability of peptides to support cell survival has never been investigated in hPSCs. In this study, we focused on the Arg-Gly-Asp (RGD) sequence and integrin receptors, which constitute the major recognition system for cell adhesion. Several new RGD-containing peptides were designed by altering the amino acids surrounding the RGD sequence. We investigated the ability of these peptides to sustain hPSC survival, and identified the Ac-KGGPQVTRGDTYRAY sequence, which was capable of supporting cell reprogramming, long-term self-renewal and lineage differentiation. In addition, this report demonstrates that the introduction of mutations in the amino acids surrounding the RGD sequence is a good strategy to design peptides that display excellent adhesion properties and promote hPSC self-renewal. Our results will help improve the current understanding of the mechanisms by which RGD-containing peptides exhibit different abilities in sustaining hPSC culture, and will promote clinical application of both peptide displaying surfaces and hPSCs.


Assuntos
Oligopeptídeos/farmacologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Oligopeptídeos/química , Tamanho da Partícula , Relação Estrutura-Atividade , Propriedades de Superfície
19.
Bioorg Med Chem ; 26(12): 3217-3226, 2018 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-29705376

RESUMO

A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2-4.6 µM, while the IC50 value of reference compound VX-680 was 8.5-15.3 µM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118 ±â€¯8.1 and 80 ±â€¯4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.


Assuntos
Aurora Quinases/antagonistas & inibidores , Ftalazinas/química , Inibidores de Proteínas Quinases/síntese química , Aurora Quinases/metabolismo , Sítios de Ligação , Proteína Quinase CDC2/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/metabolismo , Regulação para Baixo/efeitos dos fármacos , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Ftalazinas/metabolismo , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
20.
Chem Biol Drug Des ; 92(1): 1357-1365, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29624884

RESUMO

The coreceptor binding site of gp120 plays an important role in HIV entry into host cell. X5 and 17b are typical coreceptor binding site antibodies with the ability to broadly neutralize HIV. Thus, here, to study the neutralizing mechanism of two antibodies and identify the source of two antibodies with different neutralizing ability, we performed molecular dynamics simulations for the complexes of X5 and 17b with gp120 and CD4. The simulation results indicate X5 and 17b mainly affects CD4 and coreceptor binding sites. Specifically, for CD4 binding site (CD4bs), the binding of antibodies has different effects on CD4bs with and without CD4. However, for coreceptor binding sites, the binding of the antibodies has consistent influence on the region adjacent to loop V3 despite of the simulated systems with or without CD4. The binding of the antibodies enhances the interactions of gp120 region adjacent to loop V3 with other region of gp120, which are unfavorable for conformational rearrangements of the region adjacent to loop V3 and further binding the coreceptor. Additionally, the interactions of loop V3 and bridging sheet with X5 lead to the close motion of loop V3 in X5 bound form, which further influences the rearrangements in gp120.


Assuntos
Anticorpos Neutralizantes/imunologia , Antígenos CD4/metabolismo , Proteína gp120 do Envelope de HIV/imunologia , Sítios de Ligação , Antígenos CD4/química , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Humanos , Simulação de Dinâmica Molecular , Análise de Componente Principal , Ligação Proteica , Estrutura Terciária de Proteína
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