Unravelling the myth surrounding sterol biosynthesis as plausible target for drug design against leishmaniasis

Sakyi, Patrick O.; Amewu, Richard K.; Devine, Robert N. O. A.; Bienibuor, Alfred K.; Miller, Whelton A.; Kwofie, Samuel K.

doi:10.1007/s12639-021-01390-1

Cited by 6 publications

(5 citation statements)

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“…It is estimated to affect over 10 million people and cause up to 30,000 deaths annually ( Hernández-Bojorge et al., 2020 ). The present chemotherapeutic options comprising pentavalent antimony, pentamidine (PTM), amphotericin B (Amp B), miltefosine (Milt), paromomycin, and liposomal Amp B suffer from numerous inefficiencies such as long treatment durations, cytotoxicity, resistance, and high cost, necessitating the urgent need for alternative therapeutic agents ( Ghorbani and Farhoudi, 2018 ; Sakyi et al, 2021a ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, genetic ablation studies of 24-SMT orthologs involved in the sterol biosynthetic pathway have demonstrated that ergosterol, one of the widely recognized classes of lipids in the cellular membrane of protozoans, plays a significant role in plasma membrane stabilization and mitochondrion function ( Mukherjee et al., 2019 ). Studies have demonstrated the crucial functions of SMT to Leishmania survival, and hence, it is considered as a plausible target for drug design ( Urbina et al., 1995 ; Mukherjee et al., 2019 ; Sakyi et al., 2021a ). For instance, vaccine evaluation studies against Leishmania 24-SMT identified 24-SMT as an essential drug target ( Goto et al., 2009 ).…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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 compounds STOCK6S-65920 and STOCK6S-55084 were also predicted to be inhibitors of lanosterol 14alpha demethylase. The drugs ketoconazole, fluconazole, itraconazole, and posaconazole are already in various clinical stages for leishmaniasis treatment targeting the Leishmania parasites lanosterol 14alpha demethylase [ 93 , 94 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

et al. 2023

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The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined In silico and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT). The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite’s membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue in the human host and its conserved nature among all Leishmania parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 μM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from −7.5 to −8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of −8.7, −8.2, and −8.0 kcal/mol, lower than 22,26-azasterol (−7.6 kcal/mol), a known LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson–Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 μM (STOCK6S-06707), 23.5 ± 1.1 μM (STOCK6S-84928), and 118.3 ± 5.8 μM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 μM and 18.1 ± 1.4 μM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.

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“…Flavonoids naturally inhibit P-glycoprotein and its related ABC transporters in Leishmania . Synthetic flavonoid dimers were employed to overcome antimony drug resistance in L. donovani , enhancing intracellular drug accumulation. , Heat shock proteins (HSP70) were found to play a function in antimony tolerance by employing functional cloning to extract drug-resistance genes. Antimony and Sb(III)-resistant variant cells were found to have high levels of HSP70 proteins.…”

Section: Drug Resistance Linked To Mutationmentioning

confidence: 99%

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

Bharadava,

Upadhyay,

Kaushal

et al. 2024

ACS Omega

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Leishmaniasis, which is caused by a parasitic protozoan of the genus Leishmania, is still a major threat to global health, impacting millions of individuals worldwide in endemic areas. Chemotherapy has been the principal method for managing leishmaniasis; nevertheless, the evolution of drug resistance offers a significant obstacle to therapeutic success. Drug-resistant behavior in these parasites is a complex phenomenon including both innate and acquired mechanisms. Resistance is frequently related to changes in drug transportation, drug target alterations, and enhanced efflux of the drug from the pathogen. This review has revealed specific genetic mutations in Leishmania parasites that are associated with resistance to commonly used antileishmanial drugs such as pentavalent antimonials, miltefosine, amphotericin B, and paromomycin, resulting in changes in gene expression along with the functioning of various proteins involved in drug uptake, metabolism, and efflux. Understanding the genetic changes linked to drug resistance in Leishmania parasites is essential for creating approaches for tackling and avoiding the spread of drug-resistant variants. Based on which specific treatments focus on mutations and pathways could potentially improve treatment efficacy and help long-term leishmaniasis control. More study is needed to uncover the complete range of genetic changes generating medication resistance and to develop new therapies based on available information.

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Unravelling the myth surrounding sterol biosynthesis as plausible target for drug design against leishmaniasis

Cited by 6 publications

References 124 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

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

Genomic Insight of Leishmania Parasite: In-Depth Review of Drug Resistance Mechanisms and Genetic Mutations

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