Track topics on Twitter Track topics that are important to you
In a continuation of our computational efforts to find new natural inhibitors of a variety of target enzymes from parasites causing neglected tropical diseases (NTDs), we now report on 15 natural products (NPs) that we have identified as inhibitors of Leishmania major pteridine reductase I (LmPTR1) through a combination of in silico and in vitro investigations. Pteridine reductase (PTR1) is an enzyme of the trypanosomatid parasites' peculiar folate metabolism, and has previously been validated as a drug target. Initially, pharmacophore queries were created based on four 3D structures of LmPTR1 using co-crystallized known inhibitors as templates. Each of the pharmacophore queries was used to virtually screen a database of 1100 commercially available natural products. The resulting hits were submitted to molecular docking analyses in the substrate binding site of the respective protein structures used for the pharmacophore design. This approach led to the in silico identification of a total of 18 NPs with predicted binding affinity to LmPTR1. These compounds were subsequently tested in vitro for inhibitory activity towards recombinant LmPTR1 in a spectrophotometric inhibition assay. Fifteen out of the 18 tested compounds (hit rate = 83%) showed significant inhibitory activity against LmPTR1 when tested at a concentration of 50 µM. The IC50 values were determined for the six NPs that inhibited the target enzyme by more than 50% at 50 µM, with sophoraflavanone G being the most active compound tested (IC50 = 19.2 µM). The NPs identified and evaluated in the present study may represent promising lead structures for the further rational drug design of more potent inhibitors against LmPTR1.
This article was published in the following journal.
Name: Molecules (Basel, Switzerland)
Despite the fact that Leishmania ssp are pteridine auxotrophs, Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) inhibitors are ineffective against Leishmania major. On the other hand Pteridine R...
Incriminating new rodent species, as reservoir hosts of Leishmania parasites is crucial for understanding the transmission cycle of cutaneous leishmaniasis in Tunisia. Ctenodactylus (C.) gundi was pre...
Mercury accumulates in kidneys and produces acute kidney injury. Semen cassiae (SC), a widely consumed tea and herbal medicine in Eastern Asia, has been reported to have protective effects on kidneys....
In Tunisia, chronic cutaneous leishmaniasis due to Leishmania tropica is an important health problem. Its spreading has not been fully elucidated. Information on sandfly vectors, as well as their asso...
The province of Pichincha in Ecuador is an endemic area of cutaneous leishmaniasis, where anthropophilic sand flies with natural infection by Leishmania, have been reported as vectors. However, the ro...
The purpose of this study is to determine how the body defends itself against Leishmania (Viannia), a parasite that can cause a skin infection and skin sores. Certain cells in the immune s...
Cutaneous leishmaniasis (CL) is endemic in Israel and is caused by Leishmania major or Leishmania tropica. CL is usually a benign disease and limited to the skin. One of the local treatmen...
The efficacy of LtSTA as a skin test antigen depends upon the sensitivity and specificity of the product. This study has been designed to determine if a 15, 30, or 50µg dose shows non-spe...
PRECISE is a study to discover new detection, prognosis and treatment biomarkers for cancer. This is a prospective, multi-center, observational study designed to collect de-identified bios...
Development of a safe and effective vaccine against leishmaniasis started more than 10 years ago under WHO/TDR supervision. An autoclaved L. major vaccine (ALM) mixed with BCG has been te...
A parasitic hemoflagellate of the subgenus Leishmania leishmania that has been found as a natural infection of the Brazilian guinea pig. Its host-tissue relationship is, in general, comparable to that of L. braziliensis.
A genus of flagellate protozoa comprising several species that are pathogenic for humans. Organisms of this genus have an amastigote and a promastigote stage in their life cycles. As a result of enzymatic studies this single genus has been divided into two subgenera: Leishmania leishmania and Leishmania viannia. Species within the Leishmania leishmania subgenus include: L. aethiopica, L. arabica, L. donovani, L. enrietti, L. gerbilli, L. hertigi, L. infantum, L. major, L. mexicana, and L. tropica. The following species are those that compose the Leishmania viannia subgenus: L. braziliensis, L. guyanensis, L. lainsoni, L. naiffi, and L. shawi.
A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and animals and causes cutaneous leishmaniasis (LEISHMANIASIS, CUTANEOUS) of the Old World. Transmission is by Phlebotomus sandflies.
A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and animals and causes visceral leishmaniasis (LEISHMANIASIS, VISCERAL). The sandfly genera Phlebotomus and Lutzomyia are the vectors.
A parasitic hemoflagellate of the subgenus Leishmania leishmania that infects man and rodents. This taxonomic complex includes species which cause a disease called Oriental sore which is a form of cutaneous leishmaniasis (LEISHMANIASIS, CUTANEOUS) of the Old World.
Tropical Medicine is the study of diseases more commonly found in tropical regions than elsewhere. Examples of these diseases are malaria, yellow fever, Chagas disease, Dengue, Helminths, African trypanosomiasis, Leishmaniasis, Leprosy, Lymphatic filaria...
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...
Within medicine, nutrition (the study of food and the effect of its components on the body) has many different roles. Appropriate nutrition can help prevent certain diseases, or treat others. In critically ill patients, artificial feeding by tubes need t...