Brazilian malaria molecular targets (BraMMT): selected receptors for virtual high-throughput screening experiments

BACKGROUND Owing to increased spending on pharmaceuticals since 2010, discussions about rising costs for the development of new medical technologies have been focused on the pharmaceutical industry. Computational techniques have been developed to reduce costs associated with new drug development. Among these techniques, virtual high-throughput screening (vHTS) can contribute to the drug discovery process by providing tools to search for new drugs with the ability to bind a specific molecular target. OBJECTIVES In this context, Brazilian malaria molecular targets (BraMMT) was generated to execute vHTS experiments on selected molecular targets of Plasmodium falciparum. METHODS In this study, 35 molecular targets of P. falciparum were built and evaluated against known antimalarial compounds. FINDINGS As a result, it could predict the correct molecular target of market drugs, such as artemisinin. In addition, our findings suggested a new pharmacological mechanism for quinine, which includes inhibition of falcipain-II and a potential new antimalarial candidate, clioquinol. MAIN CONCLUSIONS The BraMMT is available to perform vHTS experiments using OCTOPUS or Raccoon software to improve the search for new antimalarial compounds. It can be retrieved from www.drugdiscovery.com.br or download of Supplementary data.

Successful application of virtual screening and molecular dynamics simulations against antimalarial molecular targets

The main challenge in the control of malaria has been the emergence of drug-resistant parasites. The presence of drug-resistant Plasmodium sp. has raised the need for new antimalarial drugs. Molecular modelling techniques have been used as tools to develop new drugs. In this study, we employed virtual screening of a pyrazol derivative (Tx001) against four malaria targets: plasmepsin-IV, plasmepsin-II, falcipain-II, and PfATP6. The receiver operating characteristic curves and area under the curve (AUC) were established for each molecular target. The AUC values obtained for plasmepsin-IV, plasmepsin-II, and falcipain-II were 0.64, 0.92, and 0.94, respectively. All docking simulations were carried out using AutoDock Vina software. The ligand Tx001 exhibited a better interaction with PfATP6 than with the reference compound (-12.2 versus -6.8 Kcal/mol). The Tx001-PfATP6 complex was submitted to molecular dynamics simulations in vacuum implemented on an NAMD program. The ligand Tx001 docked at the same binding site as thapsigargin, which is a natural inhibitor of PfATP6. Compound TX001 was evaluated in vitro with a P. falciparum strain (W2) and a human cell line (WI-26VA4). Tx001 was discovered to be active against P. falciparum (IC50 = 8.2 µM) and inactive against WI-26VA4 (IC50 > 200 µM). Further ligand optimisation cycles generated new prospects for docking and biological assays.

Structure-based drug design studies of the interactions of ent-kaurane diterpenes derived from Wedelia paludosa with the Plasmodium falciparum sarco/endoplasmic reticulum Ca2+-ATPase PfATP6

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Construção do receptor CYSLTR1 por modelagem comparativa / Building of CYSLTR1 receptor by comparative modeling

A asma é caracterizada como um distúrbio inflamatório crônico das vias aéreas, provocada pela contração da musculatura lisa dos bronquíolos, ocasionando obstrução parcial dos mesmos e dificultando a respiração. A Organização Mundial de Saúde (OMS) estima que 300 milhões de pessoas atualmente sofram de asma, sendo que as crianças estão entre as mais acometidas. Somente em 2005, 255.000 pessoas morreram de asma. Dentre os mediadores envolvidos no processo asmático, os leucotrienos cisteínicos, derivados do ácido araquidônico, são considerados os mais potentes entre aqueles envolvidos no processo asmático, indicados como principais mediadores da inflamação reversível das vias aéreas. Nos últimos 20 anos, grandes esforços têm sido realizados para identificar e desenvolver antagonistas dos receptores de leucotrienos na busca de melhorar o tratamento da asma, limitar a sua morbidade, e reduzir os efeitos dos medicamentos atuais. Portanto, o presente estudo propôs a construção de um modelo teórico do receptor do leucotrienos cisteínicos denominado CysLT1 por Modelagem Comparativa. Conclui-se que o modelo obtido através das metodologias computacionais e apresentado no presente estudo pode auxiliar em futuros testes, principalmente em metodologias que empregam ancoragem molecular e de novo design testando, in silico, ligantes de diversas fontes contra o receptor CysLT1.

Asthma is a chronic inflammatory disorder of the airways characterized by contraction of the smooth muscle of the bronchioles, causing their partial obstruction and making it difficult to breathe. The World Health Organization (WHO) estimates that 300 million people currently suffer from asthma, which is more common among children. In 2005 alone, 255,000 people died of asthma. The cysteinyl leukotrienes, derived from arachidonic acid, are considered the most potent mediators of the asthmatic process, being indicated as key mediators of reversible airway inflammation. In the past 20 years, great efforts have been made to identify and develop leukotriene receptor antagonists, in the quest to improve the treatment of asthma, limit its morbidity and reduce the side-effects of current drugs. Therefore, the objective of this study was to build a theoretical model of the cysteinyl leukotriene receptor, CysLT1, by Comparative Modeling. We conclude that the model generated by computational methods and presented in this paper may help in future studies, especially where docking and de novo design are involved, in which new ligands from diverse sources are tested in silico against the CysLT1 receptor.

Estudos QSAR e Ancoragem Molecular de Inibidores da Atividade Biológica do Fator de Inibição da Migração dos Macrófagos (MIF) / QSAR Modeling and Molecular Docking Study of Inhibitors of Macrophage Migration Inhibitory Factor (MIF)

Cumarina e 4-Cromonas são promissores inibidores de fator inibição da migração de macrófagos (MIF), uma proteína envolvida em doenças inflamatórias, como artrite reumatóide e outras patologias. Estudos teóricos de QSAR e ancoragem molecular de um conjunto de compostos mostraram correlação com estudos experimentais. Os descritores doadores de ligação hidrogênio e momento dipolo total foram capazes de prever atividade inibitória de compostos contra o MIF (MIFi). Paralelamente, estudos de ancoragem molecular também foram capazes de identificar ligações hidrogênio e hidrofóbicas entre os ligantes e o MIF. Como resultado, ambas as metodologias mostraram as contribuições de ligação de hidrogênio e interações hidrofóbicas para explicar a atividade de compostos inibidores de MIF, descrevendo os grupos farmacofóricos destes compostos. Adicionalmente, um conjunto de cumarinas naturais e sintéticas foi submetido aos modelos QSAR e de ancoragem molecular a fim de que as suas atividades contra MIF fossem preditas. Ambas as metodologias de modelagem molecular puderam estimar as interações intermoleculares entre inibidores e a enzima, os quais foram muito similares a compostos descritos previamente. Estes resultados podem ser úteis para o desenho de novos compostos contra doenças inflamatórias como artrite reumatóide.

Coumarin and Chromen-4-one are promising inhibitors of Macrophage Migration Inhibitory Factor (MIF), a protein involved in rheumatoid arthritis and other inflammatory diseases. Quantum structure-activity relationship (QSAR) and docking theoretical studies were undertaken on a set of compounds of known activity and showed agreement with previous experimental studies. Two descriptors, hydrogen donor sites and the total dipole, were able to predict MIF inhibitory activity (MIFi). The docking studies corroborated the QSAR studies. As a result, both methods indicated contributions of hydrogen bonds and hydrophobic interactions that explain the activity of the MIF inhibitors, describing the pharmacophore groups these molecules. Additionally, a set of natural and synthetic coumarins was subjected to the QSAR and docking models in order to predict their possible MIF inhibitory activity. Both molecular modeling methods were able to estimate the intermolecular interactions between inhibitors and enzyme, which were very similar to those of previously described compounds. These results could be useful to design new compounds against inflammatory diseases such as rheumatoid arthritis.