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1.
Nat Commun ; 12(1): 757, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536423

RESUMO

Chordoma is a rare bone tumor with an unknown etiology and high recurrence rate. Here we conduct whole genome sequencing of 80 skull-base chordomas and identify PBRM1, a SWI/SNF (SWItch/Sucrose Non-Fermentable) complex subunit gene, as a significantly mutated driver gene. Genomic alterations in PBRM1 (12.5%) and homozygous deletions of the CDKN2A/2B locus are the most prevalent events. The combination of PBRM1 alterations and the chromosome 22q deletion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-specific survival (Hazard ratio [HR] = 10.55, 95% confidence interval [CI] = 2.81-39.64, p = 0.001) and recurrence-free survival (HR = 4.30, 95% CI = 2.34-7.91, p = 2.77 × 10-6). Despite the low mutation rate, extensive somatic copy number alterations frequently occur, most of which are clonal and showed highly concordant profiles between paired primary and recurrence/metastasis samples, indicating their importance in chordoma initiation. In this work, our findings provide important biological and clinical insights into skull-base chordoma.


Assuntos
Cordoma/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Proteína SMARCB1/genética , Neoplasias da Base do Crânio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Genoma/métodos , Adulto , Cordoma/patologia , Variações do Número de Cópias de DNA , Feminino , Genômica/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Neoplasias da Base do Crânio/patologia , Adulto Jovem
2.
J Healthc Inform Res ; : 1-16, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33426422

RESUMO

Countries across the world are in different stages of COVID-19 trajectory, among which many have implemented lockdown measures to prevent its spread. Although the lockdown is effective in such prevention, it may put the economy into a depression. Predicting the epidemic progression with the government switching the lockdown on or off is critical. We propose a transfer learning approach called ALeRT-COVID using attention-based recurrent neural network (RNN) architecture to predict the epidemic trends for different countries. A source model was trained on the pre-defined source countries and then transferred to each target country. The lockdown measure was introduced to our model as a predictor and the attention mechanism was utilized to learn the different contributions of the confirmed cases in the past days to the future trend. Results demonstrated that the transfer learning strategy is helpful especially for early-stage countries. By introducing the lockdown predictor and the attention mechanism, ALeRT-COVID showed a significant improvement in the prediction performance. We predicted the confirmed cases in 1 week when extending and easing lockdown separately. Our results show that lockdown measures are still necessary for several countries. We expect our research can help different countries to make better decisions on the lockdown measures.

3.
J Chem Theory Comput ; 17(2): 1086-1097, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33503371

RESUMO

A double exponential (DE) functional form for Lennard-Jones (LJ) interactions, proposed in our previous study, has many advantages over LJ potentials including a natural softcore characteristic for the convenience of the pathway-based free-energy calculations, fast convergence, and flexibility in use. In this work, we put the first step on the application of the DE functional form by identifying a DE potential, coined DE-TIP3P, for molecular simulations using the TIP3P water model. The developed DE-TIP3 potential was better than LJ potential in reproducing the experimental water properties. Afterward, we developed the nonbonded models of 15 divalent metal ions, which frequently appear and play vital roles in biological systems, to be consistent with the DE-TIP3P potential and TIP3P water model. Our nonbonded models were as good as the complicated nonbonded dummy cationic models by Jiang et al. and the nonbonded 12-6-4 LJ models by Li and Merz in reproducing the experimental properties of those ions. Moreover, our nonbonded models achieved a better performance than the compromise (CM) LJ models and 12-6-4 LJ models, developed by Li and Merz, in reproducing the properties of MgCl2 in aqueous solution.

4.
Chem Phys Lipids ; 234: 105030, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33347835

RESUMO

Experimental studies have reported that the amyloid-ß proteins can form pores in cell membranes, and this could be one possible source of toxicity in Alzheimer's disease. Dissociation of these pores could therefore be a potential therapeutic approach. It is known that high photon density free-electron laser experiments and laser-induced nonequilibrium molecular dynamics simulations (NEMD) can dissociate amyloid fibrils at specific frequencies in vitro. Our question is whether NEMD simulations can dissociate amyloid pores in a bilayer mimicking a neuronal membrane, and as an example, we select a tetrameric Aß42 ß-barrel. Our simulations shows that the resonance between the laser field and the amide I vibrational mode of the barrel destabilises all intramolecular and intermolecular hydrogen bonds of Aß42 and converts the ß-barrel to a random/coil disordered oligomer. Starting from this disordered oligomer, extensive standard MD simulations shows sampling of disordered Aß42 states without any increase of ß-sheet and reports that the orientational order of lipids is minimally disturbed. Interestingly, the frequency to be employed to dissociate this beta-barrel is specific to the amino acid sequence. Taken together with our previous simulation results, this study indicates that infrared laser irradiation can dissociate amyloid fibrils and oligomers in bulk solution and in a membrane environment without affecting the surrounding molecules, offering therefore a promising way to retard the progression of AD.

5.
Int J Mol Sci ; 21(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228147

RESUMO

The heterodimeric ATP-binding cassette (ABC) sterol transporter, ABCG5/G8, is responsible for the biliary and transintestinal secretion of cholesterol and dietary plant sterols. Missense mutations of ABCG5/G8 can cause sitosterolemia, a loss-of-function disorder characterized by plant sterol accumulation and premature atherosclerosis. A new molecular framework was recently established by a crystal structure of human ABCG5/G8 and reveals a network of polar and charged amino acids in the core of the transmembrane domains, namely, a polar relay. In this study, we utilize genetic variants to dissect the mechanistic role of this transmembrane polar relay in controlling ABCG5/G8 function. We demonstrated a sterol-coupled ATPase activity of ABCG5/G8 by cholesteryl hemisuccinate (CHS), a relatively water-soluble cholesterol memetic, and characterized CHS-coupled ATPase activity of three loss-of-function missense variants, R543S, E146Q, and A540F, which are respectively within, in contact with, and distant from the polar relay. The results established an in vitro phenotype of the loss-of-function and missense mutations of ABCG5/G8, showing significantly impaired ATPase activity and loss of energy sufficient to weaken the signal transmission from the transmembrane domains. Our data provide a biochemical evidence underlying the importance of the polar relay and its network in regulating the catalytic activity of ABCG5/G8 sterol transporter.

6.
Phys Chem Chem Phys ; 22(46): 26707-26719, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33159779

RESUMO

Pulsed electron paramagnetic resonance (EPR) based distance measurements using the recently developed Cu2+-DPA label present a promising strategy for measuring DNA backbone distance constraints. Herein we develop force field parameters for Cu2+-DPA in order to understand the features of this label at an atomic level. We perform molecular dynamics (MD) simulations using the force field parameters of Cu2+-DPA on four different DNA duplexes. The distance between the Cu2+ centers, extracted from the 2 µs MD trajectories, agrees well with the experimental distance for all the duplexes. Further analyses of the trajectory provide insight into the orientation of the Cu2+-DPA inside the duplex that leads to such agreement with experiments. The MD results also illustrate the ability of the Cu2+-DPA to report on the DNA backbone distance constraints. Furthermore, measurement of fluctuations of individual residues showed that the flexibility of Cu2+-DPA in a DNA depends on the position of the label in the duplex, and a 2 µs MD simulation is not sufficient to fully capture the experimental distribution in some cases. Finally, the MD trajectories were utilized to understand the key aspects of the double electron electron resonance (DEER) results. The lack of orientational selectivity effects of the Cu2+-DPA at Q-band frequency is rationalized in terms of fluctuations in the Cu2+ coordination environment and rotameric fluctuations of the label linker. Overall, a combination of EPR and MD simulations based on the Cu2+-DPA labelling strategy can contribute towards understanding changes in DNA backbone conformations during protein-DNA interactions.

7.
J Chem Inf Model ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213150

RESUMO

With continually increased computer power, molecular mechanics force field-based approaches, such as the endpoint methods of molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA), have been routinely applied in both drug lead identification and optimization. However, the MM-PB/GBSA method is not as accurate as the pathway-based alchemical free energy methods, such as thermodynamic integration (TI) or free energy perturbation (FEP). Although the pathway-based methods are more rigorous in theory, they suffer from slow convergence and computational cost. Moreover, choosing adequate perturbation routes is also crucial for the pathway-based methods. Recently, we proposed a new method, coined extended linear interaction energy (ELIE) method, to overcome some disadvantages of the MM-PB/GBSA method to improve the accuracy of binding free energy calculation. In this work, we have systematically assessed this approach using in total 229 protein-ligand complexes for eight protein targets. Our results showed that ELIE performed much better than the molecular docking and MM-PBSA method in terms of root-mean-square error (RMSE), correlation coefficient (R), predictive index (PI), and Kendall's τ. The mean values of PI, R, and τ are 0.62, 0.58, and 0.44 for ELIE calculations. We also explored the impact of the length of simulation, ranging from 1 to 100 ns, on the performance of binding free energy calculation. In general, extending simulation length up to 25 ns could significantly improve the performance of ELIE, while longer molecular dynamics (MD) simulation does not always perform better than short MD simulation. Considering both the computational efficiency and achieved accuracy, ELIE is adequate in filling the gap between the efficient docking methods and computationally demanding alchemical free energy methods. Therefore, ELIE provides a practical solution for the routine ranking of compounds in lead optimization.

8.
Toxicon ; 189: 10-18, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181164

RESUMO

More and more studies have showed that tricothecene mycotoxin, deoxynivalenol (DON) caused cytotoxicity in mammary alveolar cells-large T antigen cells (MAC-T). Therefore, research on reducing the cytotoxicity of DON has gradually attracted attention. In this study, we aim to explore the potential of pterostilbene (PTE) to protect MAC-T cells from DON-induced oxidative stress and inflammatory response. MAC-T cells were treated with 0.25 µg/mL DON or 2.0504 µg/mL PTE or 0.25 µg/mL DON and 2.0504 µg/mL PTE together, incubated for 9 h. PTE effectively improved cell viability, cell proliferation and total antioxidant capacity (T-AOC), reduced reactive oxygen species (ROS) production and malondialdehyde (MDA), and improved glutathione (GSH) depletion. Moreover, PTE effectively regulated the mRNA levels of nuclear factor erythroid-2-related factor 2 (Nrf2), kelch-like ech-associated protein 1 (Keap1), superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2). PTE significantly inhibited nuclear factor kappa-B P65 (NF-κB P65), nuclear factor kappa-B P50 (NF-κB P50), cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) mRNA levels in DON-induced MAC-T cells. PTE also significantly reduced inducible nitric oxide synthase (iNOS) and nitric oxide (NO) levels in DON-induced MAC-T cells. Additionally, ELISA revealed that PTE inhibited the expression of tumor necrosis factor-α (TNF-α) and IL-6 proteins produced in DON-induced MAC-T cells. These findings together provided strong evidence to support that PTE can effectively alleviate the damage to cells caused by DON, and it may be used as an effective anti-inflammatory and antioxidant to prevent the damage of mycotoxins to the animal body.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33239215

RESUMO

Semiconductor-based photocatalytic hydrogen evolution is considered to be a promising and cost-effective approach to address the environmental issues and energy crisis. It still remains a great challenge to design highly-efficient semiconductor photocatalysts via a facile method. Herein, hierarchically porous hydrangea-like In2S3/In2O3 heterostructures are successfully synthesized via a simple in situ oxidization process. The formed In2S3/In2O3 heterostructures exhibit superior photocatalytic activity to the counterpart In2S3 and In2O3. The boosted photocatalytic performance is ascribed to the formed heterostructures, which greatly facilitate the interfacial charge transfer. Moreover, the formation of hierarchically porous heterostructures increases the number of active sites and improves the permeability, and thus significantly promotes the photocatalytic H2 evolution activity. This work may provide a new insight for designing In2S3-based heterostructures for efficient solar light conversion.

10.
J Chem Phys ; 153(11): 114502, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32962378

RESUMO

The General AMBER Force Field (GAFF) has been broadly used by researchers all over the world to perform in silico simulations and modelings on diverse scientific topics, especially in the field of computer-aided drug design whose primary task is to accurately predict the affinity and selectivity of receptor-ligand binding. The atomic partial charges in GAFF and the second generation of GAFF (GAFF2) were originally developed with the quantum mechanics derived restrained electrostatic potential charge, but in practice, users usually adopt an efficient charge method, Austin Model 1-bond charge corrections (AM1-BCC), based on which, without expensive ab initio calculations, the atomic charges could be efficiently and conveniently obtained with the ANTECHAMBER module implemented in the AMBER software package. In this work, we developed a new set of BCC parameters specifically for GAFF2 using 442 neutral organic solutes covering diverse functional groups in aqueous solution. Compared to the original BCC parameter set, the new parameter set significantly reduced the mean unsigned error (MUE) of hydration free energies from 1.03 kcal/mol to 0.37 kcal/mol. More excitingly, this new AM1-BCC model also showed excellent performance in the solvation free energy (SFE) calculation on diverse solutes in various organic solvents across a range of different dielectric constants. In this large-scale test with totally 895 neutral organic solvent-solute systems, the new parameter set led to accurate SFE predictions with the MUE and the root-mean-square-error of 0.51 kcal/mol and 0.65 kcal/mol, respectively. This newly developed charge model, ABCG2, paved a promising path for the next generation GAFF development.

11.
J Chem Phys ; 153(11): 114116, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32962395

RESUMO

Molecular dynamics simulations of biomolecules have been widely adopted in biomedical studies. As classical point-charge models continue to be used in routine biomolecular applications, there have been growing demands on developing polarizable force fields for handling more complicated biomolecular processes. Here, we focus on a recently proposed polarizable Gaussian Multipole (pGM) model for biomolecular simulations. A key benefit of pGM is its screening of all short-range electrostatic interactions in a physically consistent manner, which is critical for stable charge-fitting and is needed to reproduce molecular anisotropy. Another advantage of pGM is that each atom's multipoles are represented by a single Gaussian function or its derivatives, allowing for more efficient electrostatics than other Gaussian-based models. In this study, we present an efficient formulation for the pGM model defined with respect to a local frame formed with a set of covalent basis vectors. The covalent basis vectors are chosen to be along each atom's covalent bonding directions. The new local frame can better accommodate the fact that permanent dipoles are primarily aligned along covalent bonds due to the differences in electronegativity of bonded atoms. It also allows molecular flexibility during molecular simulations and facilitates an efficient formulation of analytical electrostatic forces without explicit torque computation. Subsequent numerical tests show that analytical atomic forces agree excellently with numerical finite-difference forces for the tested system. Finally, the new pGM electrostatics algorithm is interfaced with the particle mesh Ewald (PME) implementation in Amber for molecular simulations under the periodic boundary conditions. To validate the overall pGM/PME electrostatics, we conducted an NVE simulation for a small water box of 512 water molecules. Our results show that to achieve energy conservation in the polarizable model, it is important to ensure enough accuracy on both PME and induction iteration. It is hoped that the reformulated pGM model will facilitate the development of future force fields based on the pGM electrostatics for applications in biomolecular systems and processes where polarization plays crucial roles.

12.
J Chem Phys ; 153(4): 045104, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32752695

RESUMO

The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas.

13.
J Phys Chem B ; 124(35): 7544-7556, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32790374

RESUMO

Peptide nucleic acids (PNAs) are a promising group of synthetic analogues of DNA and RNA that offer several distinct advantages over the naturally occurring nucleic acids for applications in biosensing, drug delivery, and nanoelectronics. Because of its structural differences from DNA/RNA, methods to analyze and assess the structure, conformations, and dynamics are needed. In this work, we develop synergistic techniques for the study of the PNA conformation. We use CuQ2, a Cu2+ complex with 8-hydroxyquinoline (HQ), as an alternative base pair and as a spin label in electron paramagnetic resonance (EPR) distance methods. We use molecular dynamics (MD) simulations with newly developed force field parameters for the spin labels to interpret the distance constraints determined by EPR. We complement these methods by UV-vis and circular dichroism measurements and assess the efficacy of the Cu2+ label on a PNA duplex whose backbone is based on aminoethylglycine and a duplex with a hydroxymethyl backbone modification. We show that the Cu2+ label functions efficiently within the standard PNA and the hydroxymethyl-modified PNA and that the MD parameters may be used to accurately reproduce our EPR findings. Through the combination of EPR and MD, we gain new insights into the PNA structure and conformations as well as into the mechanism of orientational selectivity in Cu2+ EPR at X-band. These results present for the first time a rigid Cu2+ spin label used for EPR distance measurements in PNA and the accompanying MD force fields for the spin label. Our studies also reveal that the spin labels have a low impact on the structure of the PNA duplexes. The combined MD and EPR approach represents an important new tool for the characterization of the PNA duplex structure and provides valuable information to aid in the rational application of PNA at large.

14.
J Clin Pharm Ther ; 45(5): 1076-1086, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32627223

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Although ticagrelor has been well-known to improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI), and its effectiveness and safety have not been well evaluated in Chinese patients. This study aimed to evaluate the effectiveness and safety of ticagrelor in Chinese patients. In order to find potential effect modifiers on the drug effects, a decision tree method was performed to detect interactions between treatment and patient characteristics in an automatic and systematic manner. METHODS: This retrospective study included acute coronary syndrome (ACS) patients who underwent PCI and received either ticagrelor (N = 250) or clopidogrel (N = 291) while hospitalized between August 2014 and August 2015. After propensity score matching, Kaplan-Meier analysis was used to study the event-free survival against major adverse cardiovascular events (MACE, primary efficacy outcome, defined as the composite of cardiac death, non-fatal myocardial infarction [MI], stroke, restenosis and target vessel revascularization [TVR]), re-hospitalization, the need for urgent re-PCI (secondary efficacy outcome) and bleeding events (safety outcome) within 12 months of the PCI date. To search for effect modifiers of the two antiplatelet therapies, a machine-learning decision tree algorithm was conducted to predict re-hospitalization status. RESULTS: After propensity score matching (N = 442), ticagrelor and clopidogrel had no significant difference in MACE, re-hospitalization and bleeding. The decision tree analysis showed that the number of diseased vessels modulated the effect of ticagrelor and clopidogrel on re-hospitalization rates. In single-vessel disease (SVD) patients, ticagrelor was associated with lower hazards than clopidogrel for all efficacy outcomes: MACE (HR = 0.190, 95% CI: 0.042-0.866), re-hospitalization (HR = 0.296, 95% CI: 0.108-0.808), urgent re-PCI (HR = 0.249, 95% CI: 0.069-0.895), bleeding (HR = 1.006, 95% CI: 0.063-16.129). However, in multi-vessel disease (MVD) patients, the two treatments did not show significant difference. WHAT IS NEW AND CONCLUSION: In the general patient population, there was no significant difference between ticagrelor and clopidogrel on the hazard of MACE. However, ticagrelor achieved a better effectiveness than clopidogrel in patients with SVD. This pilot study provides scientific basis to call for a large-scale prospective study in this population.

15.
Front Oncol ; 10: 534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32509567

RESUMO

Background: Intracranial hemangiopericytoma (IHPC) and meningioma are both meningeal neoplasms, but they have extremely different malignancy and outcomes. Because of their similar radiological characteristics, they are difficult to distinguish prior to surgery, leading to a high rate of misdiagnosis. Methods: We enrolled 292 patients (IHPC, 155; meningiomas, 137) with complete clinic-radiological and histopathological data, from a 10-year database established at Tiantan hospital. Radiomics analysis of tumor and peritumoral edema was performed on multisequence magnetic resonance images, and a fusion radiomics signature was generated using a machine-learning strategy. By combining clinic-radiological data with the fusion radiomics signature, we developed an integrated diagnostic approach that we named the IHPC and Meningioma Diagnostic Tool (HMDT). Results: The HMDT displayed remarkable diagnostic ability, with areas under the curve (AUCs) of 0.985 and 0.917 in the training and validation cohorts, respectively. The calibration curve showed excellent agreement between the diagnosis predicted by HMDT and the histological outcome, with p-values of 0.801 and 0.622 for the training and the validation cohorts, respectively. Cross-validation showed no statistical difference across three divisions of the cohort, with average AUCs of 0.980 and 0.941 for the training and validation cohorts, respectively. Stratification analysis showed consistent performance of the HMDT in distinguishing IHPC from highly misdiagnosed subgroups of grade I meningioma and angiomatous meningioma (AM) with AUCs of 0.913 and 0.914 in the validation cohorts for the two subgroups. Conclusions: By integrating clinic-radiological information with radiomics signature, the proposed HMDT could assist in preoperative diagnosis to distinguish IHPC from meningioma, providing the basis for strategic decisions regarding surgery.

16.
ChemRxiv ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32510523

RESUMO

The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3,1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS.2-4 Several promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.82 kcal/mol. Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.82 kcal/mol) is not nearly as low as that of the neutral form (-7.92 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.86 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV. The findings of this study can facilitate rational drug design targeting the COVID-19 protease.

17.
Brief Bioinform ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32510566

RESUMO

More than 48 kinase inhibitors (KIs) have been approved by Food and Drug Administration. However, drug-resistance (DR) eventually occurs, and secondary mutations have been found in the previously targeted primary-mutated cancer cells. Cancer and drug research communities recognize the importance of the kinase domain (KD) mutations for kinasopathies. So far, a systematic investigation of kinase mutations on DR hotspots has not been done yet. In this study, we systematically investigated four types of representative mutation hotspots (gatekeeper, G-loop, αC-helix and A-loop) associated with DR in 538 human protein kinases using large-scale cancer data sets (TCGA, ICGC, COSMIC and GDSC). Our results revealed 358 kinases harboring 3318 mutations that covered 702 drug resistance hotspot residues. Among them, 197 kinases had multiple genetic variants on each residue. We further computationally assessed and validated the epidermal growth factor receptor mutations on protein structure and drug-binding efficacy. This is the first study to provide a landscape view of DR-associated mutation hotspots in kinase's secondary structures, and its knowledge will help the development of effective next-generation KIs for better precision medicine.

18.
J Phys Chem B ; 124(29): 6266-6277, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32560588

RESUMO

Neurodegenerative diseases are usually characterized by plaques made of well-ordered aggregates of distinct amyloid proteins. Dissociating these very stable amyloid plaques is a critical clinical issue. In this study, we present a joint mid-infrared free electron laser experiment/nonequilibrium molecular dynamics simulation to understand the dissociation process of a representative example GNNQQNY fibril. By tuning the laser frequency to the amide I band of the fibril, the resonance takes place and dissociation is occurred. With the calculated and observed wide-angle X-ray scattering profiles and secondary structures before and after laser irradiation being identical, we can propose a dissociation mechanism with high confidence from our simulations. We find that dissociation starts in the core of the fibrils by fragmenting the intermolecular hydrogen bonds and separating the peptides and then propagates to the fibril extremities leading to the formation of unstructured expanded oligomers. We suggest that this should be a generic mechanism of the laser-induced dissociation of amyloid fibrils.

19.
Nat Commun ; 11(1): 2506, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427851

RESUMO

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.


Assuntos
Fosfoproteínas/genética , Prolactinoma/genética , Fatores de Processamento de RNA/genética , Adulto , Feminino , Humanos , Masculino , Mutação , Fosfoproteínas/metabolismo , Intervalo Livre de Progressão , Prolactina/genética , Prolactina/metabolismo , Prolactinoma/metabolismo , Prolactinoma/mortalidade , Fatores de Processamento de RNA/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Fator de Transcrição Pit-1/genética , Fator de Transcrição Pit-1/metabolismo , Adulto Jovem
20.
J Chem Inf Model ; 60(6): 3277-3286, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32315171

RESUMO

The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, Chem. Rev. 2019, 119, 9478; Wang, Curr. Comput.-Aided Drug Des. 2006, 2, 287; Wang; ; Hou J. Chem. Inf. Model., 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antibacterianos/química , Antibacterianos/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Reposicionamento de Medicamentos/economia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Pandemias , Pneumonia Viral/virologia , Inibidores de Proteases/química , Tetraciclinas/química , Tetraciclinas/farmacologia , Termodinâmica , Fatores de Tempo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
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