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1.
Acta Pharmacol Sin ; 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750073

RESUMO

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. The aberrant activation of androgen receptor (AR) signaling has been recognized as a crucial oncogenic driver for PCa and AR antagonists are widely used in PCa therapy. To develop novel AR antagonist, a machine-learning MIEC-SVM model was established for the virtual screening and 51 candidates were selected and submitted for bioactivity evaluation. To our surprise, a new-scaffold AR antagonist C2 with comparable bioactivity with Enz was identified at the initial round of screening. C2 showed pronounced inhibition on the transcriptional function (IC50 = 0.63 µM) and nuclear translocation of AR and significant antiproliferative and antimetastatic activity on PCa cell line of LNCaP. In addition, C2 exhibited a stronger ability to block the cell cycle of LNCaP than Enz at lower dose and superior AR specificity. Our study highlights the success of MIEC-SVM in discovering AR antagonists, and compound C2 presents a promising new scaffold for the development of AR-targeted therapeutics.

2.
Acta Pharmacol Sin ; 42(1): 68-76, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32457417

RESUMO

Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.


Assuntos
Clorometilcetonas de Aminoácidos/uso terapêutico , Caspase 3/metabolismo , Inibidores de Caspase/uso terapêutico , Hepatopatias/prevenção & controle , Oligopeptídeos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Clorometilcetonas de Aminoácidos/química , Animais , Apoptose/efeitos dos fármacos , Ductos Biliares/cirurgia , Inibidores de Caspase/química , Linhagem Celular Tumoral , Humanos , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Fragmentos de Peptídeos/química , Substâncias Protetoras/química , Piroptose/efeitos dos fármacos , Receptores de Estrogênio/química
3.
Drug Discov Today ; 19(12): 1836-40, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25256778

RESUMO

Chemical drugs provide alternative treatments for genetic diseases in addition to gene therapy. Inherited diseases arising from gain-of-function (GOF) or loss-of-function (LOF) mutations of certain genes can be ameliorated by the antagonists and/or agonists of the target genes. However, a premise for this chemical therapeutic strategy is that the GOF/LOF mutations in drug targets have a negligible influence on drug-target binding. Here, we analyze the disease-causing mutations [derived from Online Mendelian Inheritance in Man (OMIM)] in successful drug targets. We found that >70% of the mutations are located far from the drug-binding sites (>12 Å), and most of the other mutations are unlikely to have adverse effects on drug binding, supporting the chemical strategy for combating genetic diseases.


Assuntos
Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/genética , Humanos , Mutação
4.
J Chem Inf Model ; 53(12): 3343-51, 2013 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-24304102

RESUMO

Mutations in drug targets can alter the therapeutic effects of drugs. Therefore, evaluating the effects of single-nucleotide polymorphisms (SNPs) on drug-target binding is of significant interest. This study focuses on the analysis of the structural and energy properties of SNPs in successful drug targets by using the data derived from HapMap and the Therapeutic Target Database. The results show the following: (i) Drug targets undergo strong purifying selection, and the majority (92.4%) of the SNPs are located far from the drug-binding sites (>12 Å). (ii) For SNPs near the drug-binding pocket (≤12 Å), nearly half of the drugs are weakly affected by the SNPs, and only a few drugs are significantly affected by the target mutations. These results have direct implications for population-based drug therapy and for chemical treatment of genetic diseases as well.


Assuntos
Simulação de Acoplamento Molecular , Polimorfismo de Nucleotídeo Único , Medicamentos sob Prescrição/química , Proteínas/química , Bases de Dados Genéticas , Projeto HapMap , Humanos , Simulação de Dinâmica Molecular , Terapia de Alvo Molecular , Mutação , Proteínas/agonistas , Proteínas/antagonistas & inibidores , Proteínas/genética , Seleção Genética , Termodinâmica
5.
Biochem Biophys Res Commun ; 423(2): 319-24, 2012 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-22659414

RESUMO

Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/genética , Substituição de Aminoácidos , Quinase do Linfoma Anaplásico , Domínio Catalítico/genética , Crizotinibe , Cristalografia por Raios X , Cisteína/química , Cisteína/genética , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Mutação , Conformação Proteica , Receptores Proteína Tirosina Quinases/química , Tirosina/química , Tirosina/genética
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