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1.
EClinicalMedicine ; 67: 102372, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38169790

RESUMO

Background: The mRNA vaccine has demonstrated significant effectiveness in protecting against SARS-CoV-2 during the pandemic, including against severe forms of the disease caused by emerging variants. In this study, we examined safety, immunogenicity, and relative efficacy of a heterologous booster of the lipopolyplex (LPP)-based mRNA vaccine (SW-BIC-213) versus a homologous booster of an inactivated vaccine (BBIBP) in Laos. Methods: In this phase 3 clinical trial, which was randomized, parallel controlled and double-blinded, healthy adults aged 18 years and above were recruited from the Southern Savannakhet Provincial Hospital and Champhone District Hospital. The primary outcomes were safety and immunogenicity, with efficacy as an exploratory endpoint. Participants who were fully immunized with a two-dose inactivated vaccine for more than 6 months were assigned equally to either the SW-BIC-213 group (25 µg) or BBIBP group. The primary safety endpoint was to describe the safety profile of all participants in each group up to 6 months post-booster immunization. The primary immunogenic outcome was to demonstrate the superiority of the neutralizing antibody response, in terms of geometric mean titers (GMTs) of SW-BIC-213, compared with BBIBP 28 days after the booster dose. The exploratory efficacy endpoint aimed to assess the relative efficacy of SW-BIC-213 compared to BBIBP against virologically confirmed symptomatic COVID-19 over a 6-month period. The trial was registered with ClinicalTrials.gov (NCT05580159). Findings: Between October 10, 2022, and January 13, 2023, 1200 participants were assigned to SW-BIC-213 group and 1203 participants in the BBIBP group. All adverse reactions observed during the study were tolerable, transient, and resolved spontaneously. Solicited local reactions were the main adverse reactions in both the SW-BIC-213 group (43.8%) and BBIBP group (14.8%) (p < 0.001). Heterologous boosting with SW-BIC-213 induced higher live virus neutralizing antibodies to SARS-CoV-2 wildtype and BA.5 strains with GMTs reaching 750.1 and 192.9 than homologous boosting with BBIBP with GMTs of 131.5 (p < 0.001) and 47.5 (p < 0.001) on day 29. The statistical findings revealed that, following a period of 14-day to 6-month after booster vaccination, the SW-BIC-213 group exhibited a relative vaccine efficacy (VE) of 70.1% (95% CI: 34.2-86.4) against symptomatic COVID-19 when compared to the BBIBP group. Interpretation: A heterologous booster with the COVID-19 mRNA vaccine SW-BIC-213 manifests a favorable safety profile and proves highly immunogenic and efficacious in preventing symptomatic COVID-19 in individuals who have previously received two doses of inactivated vaccine. Funding: Shanghai Strategic Emerging Industries Development Special Fund, Biomedical Technology Support Special Project of Shanghai "Science and Technology Innovation Action Plan", Shanghai Municipal Science and Technology Commission.

2.
EBioMedicine ; 91: 104586, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37099843

RESUMO

BACKGROUND: We assessed the safety and immunogenicity of a core-shell structured lipopolyplex (LPP) based COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults. METHODS: We conducted an open-labeled, two-centered, and three-arm randomised phase 1 trial. Healthy adults, who had completed a two-dose of inactivated COVID-19 vaccine for more than six months, were enrolled and randomized to receive a booster dose of COVILO (inactivated vaccine) (n = 20) or SW-BIC-213-25µg (n = 20), or SW-BIC-213-45µg (n = 20). The primary study endpoint was adverse events within 30 days post-boosting. The secondary endpoint was the titers of binding antibodies and neutralizing antibodies against the wild-type (WT) of SARS-CoV-2 as well as variants of concern in serum. The exploratory endpoint was the cellular immune responses. This trial was registered with http://www.chictr.org.cn (ChiCTR2200060355). FINDINGS: Between Jun 6 and Jun 22, 2022, 60 participants were enrolled and randomized to receive a booster dose of SW-BIC-213 (25 µg, n = 20, or 45 µg, n = 20) or COVILO (n = 20). The baseline demographic characteristics of the participants at enrollment were similar among the treatment groups. For the primary outcome, injection site pain and fever were more common in the SW-BIC-213 groups (25 µg and 45 µg). Grade 3 fever was reported in 25% (5/20) of participants in the SW-BIC-213-45µg group but was resolved within 48 h after onset. No fatal events or adverse events leading to study discontinuation were observed. For secondary and exploratory outcomes, SW-BIC-213 elicited higher and longer humoral and cellular immune responses than that in the COVILO group. INTERPRETATION: SW-BIC-213, a core-shell structured lipopolyplex (LPP) based mRNA vaccine, was safe, tolerable, and immunogenic as a heterologous booster in healthy Chinese adults. FUNDING: Shanghai Municipal Government, the Science and Technology and Economic Commission of Shanghai Pudong New Area, and mRNA Innovation and Translation Center of Shanghai.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Adulto , Humanos , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Antivirais , China , Anticorpos Neutralizantes , Método Duplo-Cego , Vacinas de mRNA
4.
Cell Death Discov ; 3: 17051, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28845297

RESUMO

Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke. ROCKs, which belong to the serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of strokes. In this study, in vitro enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented statin-induced cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented statin-induced cerebral hemorrhage by enhancing endothelial cell-cell junctions through inhibiting the ROCK-mediated VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as hemorrhagic stroke.

5.
J Chem Inf Model ; 57(8): 1895-1906, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28749138

RESUMO

Drug-target residence time plays a vital role in drug efficacy. However, there is still no effective strategy to predict drug residence time. Here, we propose to use the optimized (or minimized) structures derived from holo-state proteins to calculate drug residence time, which could give a comparable or even better prediction accuracy compared with those calculated utilizing a large number of molecular dynamics (MD) structures based on the Poisson process. Besides, in addition to the Poisson process, one may use fewer samples for predicting residence time due to the reason that, in a large extent, the calculated drug residence time is stable and independent of the number of samples used for the prediction. With remarkably reduced computational load, the proposed strategy may be promising for large-scale drug residence time prediction, such as post-processing in virtual screening (VS) and lead compound optimization.


Assuntos
Descoberta de Drogas , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Proteínas/metabolismo , Algoritmos , Distribuição de Poisson , Conformação Proteica , Proteínas/química , Fatores de Tempo
6.
Sci Rep ; 5: 16749, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26568382

RESUMO

Rho-associated kinases (ROCKs) have been regarded as promising drug targets for the treatment of cardiovascular diseases, nervous system diseases and cancers. In this study, a novel integrated virtual screening protocol by combining molecular docking and pharmacophore mapping based on multiple ROCK1 crystal structures was utilized to screen the ChemBridge database for discovering potential inhibitors of ROCK1. Among the 38 tested compounds, seven of them exhibited significant inhibitory activities of ROCK1 (IC50 < 10 µM) and the most potent one (compound TS-f22) with the novel scaffold of 4-Phenyl-1H-pyrrolo [2,3-b] pyridine had an IC50 of 480 nM. Then, the structure-activity relationships of 41 analogues of TS-f22 were examined. Two potent inhibitors were proven effective in inhibiting the phosphorylation of the downstream target in the ROCK signaling pathway in vitro and protecting atorvastatin-induced cerebral hemorrhage in vivo. The high hit rate (28.95%) suggested that the integrated virtual screening strategy was quite reliable and could be used as a powerful tool for identifying promising active compounds for targets of interest.


Assuntos
Inibidores de Proteínas Quinases/química , Piridinas/química , Pirróis/química , Quinases Associadas a rho/antagonistas & inibidores , Fatores de Despolimerização de Actina/metabolismo , Amidas/química , Amidas/metabolismo , Animais , Atorvastatina/farmacologia , Sítios de Ligação , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/prevenção & controle , Bases de Dados de Compostos Químicos , Bases de Dados de Proteínas , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Piridinas/metabolismo , Piridinas/uso terapêutico , Pirróis/metabolismo , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Peixe-Zebra , Quinases Associadas a rho/metabolismo
7.
Sci Rep ; 5: 8457, 2015 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-25678308

RESUMO

How does a type II inhibitor bind to/unbind from a kinase target is still a confusing question because the small molecule occupies both the ATP pocket and the allosteric pocket of the kinase binding site. Here, by using enhanced sampling simulations (umbrella sampling, US) and two-end-state free energy calculations (MM/GSBA), we systemically studied the dissociation processes of two distinct small molecules escaping from the binding pocket of p38 MAP kinase through the allosteric channel and the ATP channel. The results show that the unbinding pathways along the allosteric channel have much lower PMF depths than those along the ATP channel, suggesting that the allosteric channel is more favorable for the dissociations of the two inhibitors and thereby supporting the general understanding that the largest channel of a target is usually the entry/exit pathway for the binding/dissociation of small molecules. Interestingly, the MM/GBSA approach yielded similar PMF profiles compared with those based on US, a much time consuming approach, indicating that for a general study, such as detecting the important transition state of a ligand binding/unbinding process, MM/GBSA may be a feasible choice.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Regulação Alostérica , Sítios de Ligação , Simulação de Dinâmica Molecular , Naftalenos/química , Naftalenos/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/química , Pirazóis/metabolismo , Termodinâmica , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Drug Discov Today ; 20(2): 267-76, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25450772

RESUMO

Farnesyltransferase (FTase) and geranylgeranyltransferase type I (GGTase-I) have crucial roles in the post-translational modifications of Ras proteins and, therefore, they are promising therapeutic targets for the treatment of various Ras-induced cancers and several other kinds of diseases. In this review, we provide an overview of the structures and biological functions of FTase and GGTase-I. Then, we summarize the typical inhibitors of FTase and GGTase-I, and highlight the drug candidates in clinical trials. In addition, we survey some recent advances in computer-aided drug design (CADD) and molecular modeling studies of FTase and GGTase-I.


Assuntos
Alquil e Aril Transferases , Farnesiltranstransferase , Alquil e Aril Transferases/antagonistas & inibidores , Alquil e Aril Transferases/química , Alquil e Aril Transferases/metabolismo , Animais , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/química , Farnesiltranstransferase/metabolismo , Humanos , Modelos Moleculares , Conformação Proteica
9.
Bioorg Med Chem Lett ; 24(23): 5470-2, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25455486

RESUMO

A simple synthesis of 2-hydroxylated (E)-stilbenes was accomplished in good yields via oxidative coupling of 2-hydroxystyrenes and arylboronic acids, with Rh(III)-catalyst and Cu(OAc)2 as oxidant. The antiproliferative evaluation of all the synthesized compounds were assessed on four different human cancer cell lines (Colo-205, MDA-468, HT29, and MGC80-3), and the results showed that several compounds exhibit strong antiproliferative activities (up to IC50=35 nM for MGC80-3).


Assuntos
Antineoplásicos/farmacologia , Estilbenos/síntese química , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Hidroxilação , Estrutura Molecular , Acoplamento Oxidativo , Estilbenos/química , Estilbenos/farmacologia
10.
Phys Chem Chem Phys ; 16(40): 22035-45, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25205360

RESUMO

With the rapid development of computational techniques and hardware, more rigorous and precise theoretical models have been used to predict the binding affinities of a large number of small molecules to biomolecules. By employing continuum solvation models, the MM/GBSA and MM/PBSA methodologies achieve a good balance between low computational cost and reasonable prediction accuracy. In this study, we have thoroughly investigated the effects of interior dielectric constant, molecular dynamics (MD) simulations, and the number of top-scored docking poses on the performance of the MM/GBSA and MM/PBSA rescoring of docking poses for three tyrosine kinases, including ABL, ALK, and BRAF. Overall, the MM/PBSA and MM/GBSA rescoring achieved comparative accuracies based on a relatively higher solute (or interior) dielectric constant (i.e. ε = 2, or 4), and could markedly improve the 'screening power' and 'ranking power' given by Autodock. Moreover, with a relatively higher solute dielectric constant, the MM/PBSA or MM/GBSA rescoring based on the best scored docking poses and the multiple top-scored docking poses gave similar predictions, implying that much computational cost can be saved by considering the best scored docking poses only. Besides, compared with the rescoring based on the minimized structures, the rescoring based on the MD simulations might not be completely necessary due to its negligible impact on the docking performance. Considering the much higher computational demand of MM/PBSA, MM/GBSA with a high solute dielectric constant (ε = 2 or 4) is recommended for the virtual screening of tyrosine kinases.


Assuntos
Simulação de Acoplamento Molecular , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/metabolismo
11.
Free Radic Biol Med ; 74: 283-93, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24973649

RESUMO

Parkinson disease (PD) is a neurodegenerative disease with multifactorial etiopathogenesis. The discovery of drug candidates that act on new targets of PD is required to address the varied pathological aspects and modify the disease process. In this study, a small compound, 2-(5-methyl-1-benzofuran-3-yl)-N-(5-propylsulfanyl-1,3,4-thiadiazol-2-yl) acetamide (MBPTA) was identified as a novel Rho-associated protein kinase inhibitor with significant protective effects against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in SH-SY5Y neuroblastoma cells. Further investigation showed that pretreatment of SH-SY5Y cells with MBPTA significantly suppressed MPP(+)-induced cell death by restoring abnormal changes in nuclear morphology, mitochondrial membrane potential, and numerous apoptotic regulators. MBPTA was able to inhibit MPP(+)-induced reactive oxygen species (ROS)/NO generation, overexpression of inducible NO synthase, and activation of NF-κB, indicating the critical role of MBPTA in regulating ROS/NO-mediated cell death. Furthermore, MBPTA was shown to activate PI3K/Akt survival signaling, and its cytoprotective effect was abolished by PI3K and Akt inhibitors. The structural comparison of a series of MBPTA analogs revealed that the benzofuran moiety probably plays a crucial role in the anti-oxidative stress action. Taken together, these results suggest that MBPTA protects against MPP(+)-induced apoptosis in a neuronal cell line through inhibition of ROS/NO generation and activation of PI3K/Akt signaling.


Assuntos
Antioxidantes/farmacologia , Benzofuranos/farmacologia , Doença de Parkinson/tratamento farmacológico , Tiadiazóis/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Acetamidas/química , Ácidos Alcanossulfônicos/química , Antioxidantes/química , Benzofuranos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citoproteção/efeitos dos fármacos , Descoberta de Drogas , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Terapia de Alvo Molecular , Proteína Oncogênica v-akt/metabolismo , Oxidantes/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Compostos de Piridínio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Tiadiazóis/química
12.
J Biol Chem ; 288(47): 34181-34189, 2013 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-24114842

RESUMO

The antiparasitic clioquinol (CQ) represents a class of novel anticancer drugs by interfering with proteasome activity. In the present study, we found that CQ induced blood cancer cell apoptosis by inhibiting histone deacetylases (HDACs). CQ accumulated the acetylation levels of several key proteins including histone H3 (H3), p53, HSP90, and α-tubulin. In the mechanistic study, CQ was found to down-regulate HDAC1, -3, -4, and -5 in both myeloma and leukemia cells. Computer modeling analysis revealed that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp-267. Moreover, co-treatment with CQ and zinc/copper chloride led to decreased Ac-H3. Furthermore, CQ inhibited the activity of Class I and IIa HDACs in the cell-free assays, demonstrating that CQ interfered with HDAC activity. By inhibiting HDAC activity, CQ induced expression of p21, p27, and p53, cell cycle arrest at G1 phase, and cell apoptosis. This study suggested that the HDAC enzymes are targets of CQ, which provided a novel insight into the molecular mechanism of CQ in the treatment of hematological malignancies.


Assuntos
Antipruriginosos/farmacologia , Apoptose/efeitos dos fármacos , Clioquinol/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Leucemia/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Cloretos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Leucemia/enzimologia , Leucemia/patologia , Masculino , Antissépticos Bucais/farmacologia , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Células U937 , Compostos de Zinco/farmacologia
13.
Drug Discov Today ; 18(23-24): 1323-33, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24076262

RESUMO

Rho-associated protein kinases (ROCK1 and ROCK2) belong to the AGC family of serine-threonine kinases, and regulate a wide range of fundamental cell functions. Inhibition of ROCK has been proven to be of potential therapeutic benefit for a variety of diseases. In this review, the structures and therapeutic importance of ROCK are discussed briefly. Then, the recent status of the development of ROCK inhibitors is also summarized. Our review offers a foundation outline from which strategies to design new leads against ROCK can be developed.


Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Humanos , Quinases Associadas a rho/metabolismo
14.
Mol Biosyst ; 9(10): 2435-46, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23881296

RESUMO

LIM kinases (LIMKs), downstream of Rho-associated protein kinases (ROCKs) and p21-activated protein kinases (PAKs), are shown to be promising targets for the treatment of cancers. In this study, the inhibition mechanism of 41 pyrrolopyrimidine derivatives as LIMK2 inhibitors was explored through a series of theoretical approaches. First, a model of LIMK2 was generated through molecular homology modeling, and the studied inhibitors were docked into the binding active site of LIMK2 by the docking protocol, taking into consideration the flexibility of the protein. The binding poses predicted by molecular docking for 17 selected inhibitors with different bioactivities complexed with LIMK2 underwent molecular dynamics (MD) simulations, and the binding free energies for the complexes were predicted by using the molecular mechanics/generalized born surface area (MM/GBSA) method. The predicted binding free energies correlated well with the experimental bioactivities (r(2) = 0.63 or 0.62). Next, the free energy decomposition analysis was utilized to highlight the following key structural features related to biological activity: (1) the important H-bond between Ile408 and pyrrolopyrimidine, (2) the H-bonds between the inhibitors and Asp469 and Gly471 which maintain the stability of the DFG-out conformation, and (3) the hydrophobic interactions between the inhibitors and several key residues (Leu337, Phe342, Ala345, Val358, Lys360, Leu389, Ile408, Leu458 and Leu472). Finally, a variety of LIMK2 inhibitors with a pyrrolopyrimidine scaffold were designed, some of which showed improved potency according to the predictions. Our studies suggest that the use of molecular docking with MD simulations and free energy calculations could be a powerful tool for understanding the binding mechanism of LIMK2 inhibitors and for the design of more potent LIMK2 inhibitors.


Assuntos
Quinases Lim/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirróis/química , Desenho de Fármacos , Concentração Inibidora 50 , Cinética , Quinases Lim/antagonistas & inibidores , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Quantitativa Estrutura-Atividade
15.
Mol Biosyst ; 9(6): 1511-21, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23549429

RESUMO

Rho kinases (ROCK1 and ROCK2) belong to serine/threonine (Ser/Thr) protein kinase family, and play the central roles in the organization of the actin cytoskeleton. Therefore, Rho kinases have become attractive targets for the treatments of many diseases, such as cancer, renal disease, hypertension, ischemia, and stroke. In order to develop small-molecule inhibitors of ROCK1, molecular docking was utilized to virtually screen two chemical databases and identify molecules that interact with ROCK1. A small set of virtual hits was purchased and submitted to a series of experimental assays. The in vitro enzyme-based and cell-based assays reveal that 12 compounds have good inhibitory activity against ROCK1 in the micro molar regime (IC50 values between about 7 and 28 µM) and antitumor activity against lung cancer, breast cancer or/and myeloma cell lines. The structural analysis shows that two active compounds present novel scaffolds and are potential leads for the development of novel anti-cancer drugs. We then characterized the interaction patterns between ROCK1 and two inhibitors with novel scaffolds by molecular dynamics (MD) simulations and free energy decomposition analysis. In addition, the pharmacological effect of the two ROCK1 inhibitors with novel scaffolds on atorvastatin-induced cerebral hemorrhage was evaluated by using zebrafish model, and one compound candidate is able to prevent atorvastatin-induced cerebral hemorrhage effectively.


Assuntos
Antineoplásicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Atorvastatina , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/tratamento farmacológico , Feminino , Células HeLa , Ácidos Heptanoicos/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirróis/farmacologia , Peixe-Zebra , Quinases Associadas a rho/metabolismo
16.
Mol Biosyst ; 9(3): 361-74, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23340525

RESUMO

Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor (1) with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three docking protocols, rigid receptor docking, induced fit docking, QM-polarized ligand docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from molecular docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue-inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor 1 were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the development of improved inhibitors of ROCK1.


Assuntos
Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Quinases Associadas a rho/antagonistas & inibidores , Motivos de Aminoácidos , Domínio Catalítico , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligação Proteica , Pirimidinas/química , Termodinâmica , Triazinas/química , Quinases Associadas a rho/química
17.
J Cheminform ; 4(1): 31, 2012 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-23181938

RESUMO

BACKGROUND: In this work, we analyzed and compared the distribution profiles of a wide variety of molecular properties for three compound classes: drug-like compounds in MDL Drug Data Report (MDDR), non-drug-like compounds in Available Chemical Directory (ACD), and natural compounds in Traditional Chinese Medicine Compound Database (TCMCD). RESULTS: The comparison of the property distributions suggests that, when all compounds in MDDR, ACD and TCMCD with molecular weight lower than 600 were used, MDDR and ACD are substantially different while TCMCD is much more similar to MDDR than ACD. However, when the three subsets of ACD, MDDR and TCMCD with similar molecular weight distributions were examined, the distribution profiles of the representative physicochemical properties for MDDR and ACD do not differ significantly anymore, suggesting that after the dependence of molecular weight is removed drug-like and non-drug-like molecules cannot be effectively distinguished by simple property-based filters; however, the distribution profiles of several physicochemical properties for TCMCD are obviously different from those for MDDR and ACD. Then, the performance of each molecular property on predicting drug-likeness was evaluated. No single molecular property shows good performance to discriminate between drug-like and non-drug-like molecules. Compared with the other descriptors, fractional negative accessible surface area (FASA-) performs the best. Finally, a PCA-based scheme was used to visually characterize the spatial distributions of the three classes of compounds with similar molecular weight distributions. CONCLUSION: If FASA- was used as a drug-likeness filter, more than 80% molecules in TCMCD were predicted to be drug-like. Moreover, the principal component plots show that natural compounds in TCMCD have different and even more diverse distributions than either drug-like compounds in MDDR or non-drug-like compounds in ACD.

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