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J Enzyme Inhib Med Chem ; 35(1): 172-186, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752564


Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (ΔG) of three screened compounds namely ZINC06823429 (-11.36 kcal/mol), ZINC95421501 (-11.29 kcal/mol), and ZINC95421070 (-11.26 kcal/mol) exhibited stronger than standard drug PF-543 (-9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.

Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Relação Estrutura-Atividade
Comput Biol Chem ; 77: 390-401, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30469054


The B-cell lymphoma-2 (Bcl-2) family proteins have been attributed to be the key regulators in programmed cell death and apoptosis with a prominent role in human cancer. Understanding the fundamental principles of cell survival and death have been the main cornerstone in cancer drug discovery for identification of novel anticancer agents. In this context the Bcl-2 family of anti-and pro-apoptotic proteins provide an excellent opportunity for development of anticancer agents, as blocking the Bcl-2 or Bcl-XL functionally promotes apoptosis in tumor cells and also sensitize them to chemo- and radiotherapies. The present study reports the identification of novel Aplysin analogs as BCL-2 inhibitors from a sequential virtual screening approach using drug-like, ADMET, docking, pharmacophore filters and molecular dynamics simulation. We identified promising Aplysin analogs that have a potential to be Bcl-2 inhibitors just like the standard drug Obatoclax. One of the compound analog 11 was identified to be a promising inhibitor of Bcl-2 in the docking, pharmacophore and simulation based models.The molecular modeling information provided here can be vital in designing of the novel Bcl-2 inhibitors.

Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Hidrocarbonetos Bromados/química , Hidrocarbonetos Bromados/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Projeto Auxiliado por Computador , Desenho de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Curr Drug Metab ; 19(6): 523-543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28228080


BACKGROUND: Malignant tumors are the leading cause of death in humans. Due to the tedious efforts and investigations made in the field of marine drug discovery, there is now a scientific bridge between marine and pharmaceutical sciences. However, currently only few marine drugs have been lined towards anticancer direction yet many more to are be established in future as well. METHOD: This review gives an overview of present status of marine natural products MNPs both at the level of research and clinical stages. The authors haved summarized the detail information of diverse marine organisms that were reportedto be active or potentially active in cancer treatment in the last two decades. Interstingly, marine organisms are abundant producer of plenty of structurally incomparable bioactive metabolites that have unusual mode of actions and diverse biosynthetic pathways. RESULTS: This review summarizes the associated anticancer properties of different classes of marine natural compounds based on their structural diversity, biological activity, and the molecular mechanisms of action. Emphasis has also be given to recent advances in clinical development of marine agents used in clinical trials. CONCLUSIONS: The present review is summarising the various sources of marine chemicals and their exploration of anticancerous potential. There is justified hope for the discovery and development of new anticancer agents from the marine environment.

Antineoplásicos , Organismos Aquáticos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico
Bioinformation ; 13(9): 293-300, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29081608


Survivin (IAP proteins) remains an important target for anticancer drug development as it is reported to be over-expressed in tumor cells to enhance resistance to apoptotic stimuli. The study focuses on virtual screening of marine compounds inhibiting survivin, a multifunctional protein, using a computational approach. Structures of compounds were prepared using ChemDraw Ultra 10. Software and converted into its 3D PDB structure and its energy was minimized using Discovery Studio client 2.5. The target protein, survivin was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling was carried out on marine compounds and the filtered compounds were further promoted for molecular docking analysis and interaction studies using AutoDock Tools 4.0. Molecular docking results revealed that analog (AP 4) of Aplysin, showed very promising inhibitory potential against survivin with a binding energy of -8.75 kcal/mol and Ki 388.28 nM as compared to its known inhibitor, Celecoxib having binding energy of -6.65 kcal/mol and Ki 13.43 µM. AP 4. The analog depicted similarity in pattern when compared to standard. The result proposes AP 4, is an effective molecule exhibiting prominent potential to inhibit survivin and thus promoting apoptosis in tumor cells.

Interdiscip Sci ; 5(2): 136-44, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23740395


Leishmaniasis is one of the most important diseases of mankind. In the life cycle of Leishmania mexicana, two most important developmental stages are observed. In insect vector it is in promastigote form and in mammalian macrophages is the amastigote form. The family of protein kinases are extremely important regulators of many different cellular processes such as transcriptional control, cell cycle development and differentiation, and also draw much attention as possible drug targets for protozaon parasites. Leishmania mexicana mitogen activated protein kinase 4 (LmxMPK4) is essential for proliferation and survival of the parasite promastigote and amastigote forms and is a potential drug target for leishmaniasis. The existing therapy for leishmaniasis is not enough due to host toxicity and drug resistance. The experimental 3D structure of this protein has not yet been determined. In this study, we have used homology modelling techniques to generate the 3D structure of LmxMPK4 and selected effective inhibitors by ZINC database on the basis of structure of berberine alkaloid for molecular docking studies with LmxMPK4. The inhibitors ZINC05999210, ZINC40402312 and ZINC40977377 were found to be more potent for inhibition of leishmaniasis due to the robust binding affinity and strong inhibition constant (Ki) of the protein-ligand interactions. This finding may help to understand the nature of MAP kinase and development of specific anti-leishmanial therapies.

Avaliação Pré-Clínica de Medicamentos , Leishmania mexicana/enzimologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/química , Inibidores de Proteínas Quinases/análise , Inibidores de Proteínas Quinases/farmacologia , Homologia Estrutural de Proteína , Sequência de Aminoácidos , Antiprotozoários/análise , Antiprotozoários/química , Antiprotozoários/farmacologia , Humanos , Leishmania mexicana/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Inibidores de Proteínas Quinases/química , Estrutura Secundária de Proteína , Alinhamento de Sequência , Análise de Sequência de Proteína , Termodinâmica , Interface Usuário-Computador