RESUMO
Decaprenylphosphoryl-ß-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 µM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.
Identification of 15 (BOK-1BOK-10 and BOP-1BOP-5) potent inhibitors of DprE1 enzyme from 1,2,3-triazole ligands.BOK-2 and BOK-3 exhibited significant DprE1 inhibition with IC50 values of 2.2 ± 0.1 and 3.0 ± 0.6 µM, respectively.Molecular modelling and dynamic simulations elucidated key structural features for effective drugtarget interactions.Novel approach introduced for designing DprE1 ligands, potentially aiding tuberculosis treatment.Findings offer promising candidates for future tuberculosis research.
Assuntos
Benzoxazóis , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos , Mycobacterium tuberculosis , Triazóis , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Benzoxazóis/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Estrutura Molecular , Fluorometria , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Modelos Moleculares , Testes de Sensibilidade Microbiana , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/metabolismoRESUMO
HER2 receptors, overexpressed in certain human cancers, have drawn significant attention in cancer research due to their correlation with poor survival rates. Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer. However, ongoing research is investigating their potential use in other types of cancer, often in combination with other medications. EGFR/HER2 dual-targeted drugs have overcome drug resistance associated with HER2-targeted monotherapy. This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.
Assuntos
Anticorpos Monoclonais , Antineoplásicos , Neoplasias , Receptor ErbB-2 , Humanos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estrutura Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismoRESUMO
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 fármacosRESUMO
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 100â ns molecular dynamic simulation study. In-vitro MAB assay revealed that 14 compounds exhibit significant antitubercular activity with minimum inhibitory concentration (MIC) of the 3.15-4.87â µM of the 20 compounds tested. An in-vitro cytotoxicity study on normal cell lines (MCF10) revealed safe compounds (IC50 values:341.85 to 726.08â 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 MicrobianaRESUMO
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 MáquinaRESUMO
Dengue virus belongs to the class of RNA viruses and subclass of enveloped single-stranded positive-sense RNA virus. It causes dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS), where DHF and DSS are life-threatening. Even though dengue is an age-old disease, it is still a mystery and continues to be a global threat. Numerous attempts have been carried out in the past few decades to eradicate the virus through vaccine and antiviral drugs, but still battle continues. In this review, the possible drug targets for discovery and development of potential antiviral drugs against structural proteins of dengue virus, the current development status of the antiviral drugs against dengue around the world, and challenges that need to be addressed to overcome the shortcomings in the process of drug discovery have been discussed.
Assuntos
Antivirais/farmacologia , Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Desenvolvimento de Medicamentos , Proteínas Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Dengue/metabolismo , Dengue/virologia , Vírus da Dengue/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Estruturais Virais/metabolismoRESUMO
Salt metathesis has been exploited to generate a series of non-steroidal anti-inflammatory drug (NSAID) based Zn(ii) metallohydrogels displaying both anti-inflammatory and anti-bacterial properties. Relatively low cytotoxicity, rheoreversibility and injectibility of one of these hydrogels make it suitable for multi-drug-self-delivery application.