The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway

Rodrigues, Jean Henrique da Silva; Miranda, Nathielle; Volpato, Hélito

doi:10.1007/s00436-018-06200-x

Cited by 20 publications

(15 citation statements)

References 38 publications

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“…For instance, compounds A1 , A2 , A3 , and A6 showed similarity scores above 0.50 to vabicaserin, sertraline, and indatraline ( Richardson et al., 2009 ; Wishart et al., 2018 ; Lima et al., 2018 ). In addition, the four compounds showed similarity scores of around 0.55, which are close to those of daledalin, zanapezil, clocapramine, imipramine, and dimethacrine ( Figure 8 ) ( Mukherjee et al., 2012 ; da Silva Rodrigues et al., 2019 ). Interestingly, these drugs have been explored for their antileishmanial potentials causing Leishmania parasites to undergo mitochondrion depolarization in addition to inhibiting trypanothione reductase, thereby inducing strong oxidative stress in the parasite ( Kaur, 2013 ; Andrade-Neto et al., 2016 ; da Silva Rodrigues et al., 2019 ).…”

Section: Resultsmentioning

confidence: 63%

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

Sakyi

Broni

Amewu

et al. 2022

Front. Cell. Infect. Microbiol.

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The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. Leishmania donovani 24-sterol methyltransferase (LdSMT) is vital for the synthesis of ergosterols, the main constituents of Leishmania cellular membranes. So far, mammals have not been shown to possess SMT or ergosterols, making the pathway a prime candidate for drug discovery. The structural model of LdSMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors via virtual screening, scaffold hopping, and de-novo fragment-based design. Altogether, six potential novel inhibitors were identified with binding energies ranging from −7.0 to −8.4 kcal/mol with e-LEA3D using 22,26-azasterol and S1–S4 obtained from scaffold hopping via the ChEMBL, DrugBank, PubChem, ChemSpider, and ZINC15 databases. These ligands showed comparable binding energy to 22,26-azasterol (−7.6 kcal/mol), the main inhibitor of LdSMT. Moreover, all the compounds had plausible ligand efficiency-dependent lipophilicity (LELP) scores above 3. The binding mechanism identified Tyr92 to be critical for binding, and this was corroborated via molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The ligand A1 was predicted to possess antileishmanial properties with a probability of activity (Pa) of 0.362 and a probability of inactivity (Pi) of 0.066, while A5 and A6 possessed dermatological properties with Pa values of 0.205 and 0.249 and Pi values of 0.162 and 0.120, respectively. Structural similarity search via DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the de-novo compounds could be explored as potential antileishmanial agents.

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Section: Resultsmentioning

confidence: 63%

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

Sakyi

Broni

Amewu

et al. 2022

Front. Cell. Infect. Microbiol.

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“…51 Another study revealed the drug-induced loss in the membrane of L. amazonensis after treatment with clomipramine. 25 Regarding these encouraging in vitro results, the effects of gallic acid in an in vivo mouse model infected with L. donovani were investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Reading of the plate was taken in a microplate reader at 535-nm and 617-nm excitation and emission wavelength, respectively. 25…”

Section: Plasma Membrane Integritymentioning

confidence: 99%

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Keshav

Goyal

Kaur

2021

Parasite Immunology

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Neglected tropical diseases (NTDs) affect nearly one-sixth of the world's population, and leishmaniasis is one such disease. The eukaryotic protozoan parasite of genus Leishmania with nearly 20 species is known to cause the disease leishmaniasis and is prevalent in nearly hundred countries throughout the world. 1 Female phlebotomine sand flies are transmission vectors of the disease. Parasite species and host immune response determine the disease outcome, and the three major manifestations are cutaneous, visceral and mucocutaneous leishmaniasis. 2 Visceral leishmaniasis (VL) is the deadliest of all the forms and is ranked as one of the world's leading parasitic killers with approximately 600 million people at risk across the globe and 7 th in loss of disability-adjusted life years (DALYs) (DNDi reports). In the Indian subcontinent and Africa, L. donovani is the aetiological agent of VL, while in the Mediterranean Basin, it is caused by L. infantum. 3 According to World Health Organization (WHO 2018), more than 95% of VL cases are clustered in 10 countries: India,

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“…Using this strategy, Rodrigues et al . demonstrated that clomipramine (S18) had potential against L. amazonensis [65] . This medication is a tricyclic antidepressant used to treat psychiatric disorders, such as obsessive‐compulsive disorder [66] .…”

Section: Drug Repurposingmentioning

confidence: 99%

“…In this study, Rodrigues et al . showed that both in promastigotes and amastigotes, the drug induced oxidative stress by increasing the levels of reactive oxygen species and H 2 O 2 [65] . In promastigotes, the reduction in cell size, membrane shrinkage, DNA fragmentation and exposure to phosphatidylserine, suggests cell death via apoptosis.…”

Section: Drug Repurposingmentioning

confidence: 99%

Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre‐Clinical to Clinical Findings

Santana

Oliveira

Ramos

et al. 2021

Chemistry & Biodiversity

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Leishmaniasis is a group of tropical diseases caused by parasitic protozoa belonging to the genus Leishmania. The disease is categorized in cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), and visceral leishmaniasis (VL). The conventional treatment is complex and can present high toxicity and therapeutic failures. Thus, there is a continuing need to develop new treatments. In this review, we focus on the novel molecules described in the literature with potential leishmanicidal activity, categorizing them in pre‐clinical (in vitro, in vivo), drug repurposing and clinical research.

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The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway

Cited by 20 publications

References 38 publications

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

Antileishmanial potential of immunomodulator gallic acid against experimental murine visceral leishmaniasis

Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre‐Clinical to Clinical Findings

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