RESUMO
Visceral leishmaniasis is a neglected tropical disease and is mainly caused by L. donovani in the Indian subcontinent. The mitochondria genome replication in Leishmania spp. is having a very specific mechanism, and it is initiated by a key enzyme called mitochondrial primase. This enzyme is essential for the onset of the replication process and growth of the parasite. Therefore, we focused on the primase protein as a potential therapeutic target for combating leishmaniasis diseases. We started our studies molecular modeling and followed by docking of the FDA-approved drug library into the binding site of the primase protein. The top 30 selected compounds were subjected for molecular dynamics studies. Also, the target protein was cloned, purified, and tested experimentally (primase activity assays and inhibition assays). Some compounds were very effective against the Leishmania cell culture. All these approaches helped us to identify few possible novel anti-leishmanial drugs such as Pioglitazone and Mupirocin. These drugs are effectively involved in inhibiting the promastigote of L. donovani, and it can be utilized in the next level of clinical trials. Communicated by Ramaswamy H. Sarma.
Assuntos
Antiprotozoários , Leishmania donovani , Leishmania , Leishmaniose Visceral , Humanos , Reposicionamento de Medicamentos , Antiprotozoários/farmacologia , Antiprotozoários/química , Avaliação Pré-Clínica de Medicamentos , DNA Primase/metabolismo , DNA Primase/farmacologia , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Simulação de Dinâmica MolecularAssuntos
Aldose-Cetose Isomerases/antagonistas & inibidores , Aldose-Cetose Isomerases/química , Antimaláricos/química , Antimaláricos/farmacologia , Modelos Moleculares , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , Aminoácidos , Sítios de Ligação , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The alignment of the evolutionary history of parasites with that of plants provides a different panorama in the drug development process. The housing of different metabolic processes, essential for parasite survival, adds to the indispensability of the apicoplast. The different pathways responsible for fueling the apicoplast and parasite offer a myriad of proteins responsible for the apicoplast function. The studies emphasizing the target-based approaches might help in the discovery of antimalarials. The different putative drug targets and their roles are highlighted. In addition, the origin of the apicoplast and metabolic processes are reviewed and the different drugs acting upon the enzymes of the apicoplast are discussed.
Assuntos
Antimaláricos/uso terapêutico , Apicoplastos/metabolismo , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Antimaláricos/farmacologia , Ácidos Graxos/metabolismo , Fluxo Gênico , Heme/metabolismo , Plasmodium falciparum/genética , Terpenos/metabolismoRESUMO
Visceral leishmaniasis (VL) has been considered as one of the most fatal form of leishmaniasis which affects 70 countries worldwide. Increased drug resistance in Indian subcontinent urged the need of new antileishmanial compounds with high efficacy and negligible toxicity. Imipramine compounds have shown impressive antileishmanial activity. To find out most potent analogue from imipramine series and explore the inhibitory activity of imipramine, we docked imipramine analogues (n=93,328) against trypanothione reductase in three sequential modes. Furthermore, 98 ligands having better docking score than reference ligand were subjected to ADME and toxicity, binding energy calculation and docking validation. Finally, Molecular dynamic and single point energy was estimated for best two ligands. This study uncovers the inhibitory activity of imipramine against Leishmania parasites.