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1.
Future Med Chem ; 16(8): 769-790, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38578146

RESUMO

Aim: Breast cancer has been a leading cause of mortality among women worldwide in recent years. Targeting the lysophosphatidic acid (LPA)-LPA1 pathway using small molecules could improve breast cancer therapy. Materials & methods: Thiazolidin-4-ones were developed and tested on MCF-7 cancer cells, and active compounds were analyzed for their effects on apoptosis, migration angiogenesis and LPA1 protein and gene expression. Results & conclusion: Compounds TZ-4 and TZ-6 effectively reduced the migration of MCF-7 cells, and induced apoptosis. TZ-4, TZ-6, TZ-8 and TZ-14 significantly reduced the LPA1 protein, LPA1 and angiogenesis gene expression in treated MCF-7 cells. Molecular docking and molecular dynamic simulation studies reveal the ligand interactions and stability of the LPA1-ligand complex. Developed thiazolidin-4-ones showed great potential as an LPA1-targeted approach to combating breast cancer.


Breast cancer is a major cause of death for women worldwide. Using small molecules to target the lysophosphatidic acid (LPA)­LPA1 pathway could improve breast cancer treatment. We tested a type of molecule called thiazolidin-4-ones on breast cancer cells in the lab. We looked at how these molecules affected cell death, movement, blood vessel growth and the activity of the LPA1 gene and protein. Some of these molecules, such as TZ-4 and TZ-6, reduced the movement of cancer cells and caused them to die. They also decreased the levels of LPA1 protein and gene activity in the cells. We used computer simulations to see how these molecules interacted with the LPA1 protein. Our findings suggest that thiazolidin-4-ones could be a promising treatment for breast cancer by targeting LPA1.


Assuntos
Antineoplásicos , Neoplasias da Mama , Desenho de Fármacos , Receptores de Ácidos Lisofosfatídicos , Tiazolidinas , Humanos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tiazolidinas/farmacologia , Tiazolidinas/química , Tiazolidinas/síntese química , Apoptose/efeitos dos fármacos , Simulação de Acoplamento Molecular , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Movimento Celular/efeitos dos fármacos
2.
Future Med Chem ; 15(22): 2087-2112, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37877348

RESUMO

Functional inactivation of wild-type p53 is a major trait of cancerous cells. In many cases, such inactivation occurs by either TP53 gene mutations or due to overexpression of p53 binding partners. This review focuses on an overexpressed p53 binding partner called mortalin, a mitochondrial heat shock protein that sequesters both wild-type and mutant p53 in malignant cells due to changes in subcellular localization. Clinical evidence suggests a drastic depletion of the overall survival time of cancer patients with high mortalin expression. Therefore, mortalin-p53 sequestration inhibitors could be game changers in improving overall survival rates. This review explores the consequences of mortalin overexpression and challenges, status and strategies for accelerating drug discovery to suppress mortalin-p53 sequestration.


Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/metabolismo , Neoplasias/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo
3.
Chem Biodivers ; 20(11): e202300971, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37882429

RESUMO

Mycobacterium tuberculosis (Mtb) has numerous cell wall and non-cell wall mediated receptors for drug action, of which cell wall mediated targets were found to be more promising because of their pivotal role in bacterial protection and survival. Herein, we reported the design and synthesis of a series of pyrazole-linked triazoles based on the reported structural features of promising drug candidates that target DprE1 receptors through a Structure-based drug design (SBDD) approach (6a-6j and 7a-7j). The synthesized compounds were evaluated for their in-vitro antitubercular activity against virulent strains of Mtb H37Rv. In-silico studies revealed that most compounds exhibit binding interactions with crucial amino acids like Lys418, Tyr314, Tyr60, and Asp386 at DprE1. Furthermore, the protein-ligand (7j) shows appreciable stability compared to innate protein in a 100 ns molecular dynamic simulation study. In-vitro MAB assay revealed that 14 compounds exhibit significant antitubercular activity with minimum inhibitory concentration (MIC) of the 3.15-4.87 µM of the 20 compounds tested. An in-vitro cytotoxicity study on normal cell lines (MCF10) revealed safe compounds (IC50 values:341.85 to 726.08 µM). Hence, the present study opens the development of new pyrazole-linked triazoles as probable DprE1 inhibitors.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Triazóis/química , Desenho de Fármacos , Pirazóis/farmacologia , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana
4.
Future Med Chem ; 14(4): 245-270, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34939433

RESUMO

Predicting novel small molecule bioactivities for the target deconvolution, hit-to-lead optimization in drug discovery research, requires molecular representation. Previous reports have demonstrated that machine learning (ML) and deep learning (DL) have substantial implications in virtual screening, peptide synthesis, drug ADMET screening and biomarker discovery. These strategies can increase the positive outcomes in the drug discovery process without false-positive rates and can be achieved in a cost-effective way with a minimum duration of time by high-quality data acquisition. This review substantially discusses the recent updates in AI tools as cheminformatics application in medicinal chemistry for the data-driven decision making of drug discovery and challenges in high-quality data acquisition in the pharmaceutical industry while improving small-molecule bioactivities and properties.


Assuntos
Inteligência Artificial , Descoberta de Drogas , Barreira Hematoencefálica/metabolismo , Tomada de Decisões , Aprendizado Profundo , Sistemas de Liberação de Medicamentos , Indústria Farmacêutica , Reposicionamento de Medicamentos , Humanos , Aprendizado de Máquina
5.
Eur J Med Chem ; 222: 113574, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34126459

RESUMO

Lysophosphatidic acid (LPA) activates six LPA receptors (LPAR1-6) and regulates various cellular activities such as cell proliferation, cytoprotection, and wound healing. Many studies elucidated the pathological outcomes of LPA are due to the alteration in signaling pathways, which include migration and invasion of cancer cells, fibrosis, atherosclerosis, and inflammation. Current pathophysiological research on LPA and its receptors provides a means that LPA receptors are new therapeutic targets for disorders associated with LPA. Various chemical modulators are developed and are under investigation to treat a wide range of pathological complications. This review summarizes the physiological and pathological roles of LPA signaling, development of various LPA modulators, their structural features, patents, and their clinical outcomes.


Assuntos
Lisofosfolipídeos/farmacologia , Receptores de Ácidos Lisofosfatídicos/agonistas , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Lisofosfolipídeos/química , Lisofosfolipídeos/metabolismo , Estrutura Molecular , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
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