In silico screening, molecular dynamic simulations, and in vitro activity of selected natural compounds as an inhibitor of Leishmania donovani 3-mercaptopyruvate sulfurtransferase

Kant, Vishnu; Kumar, Pawan; Ranjan, Ravi; Kumar, Prakash; Mandal, Debabrata; Vijayakumar, Saravanan

doi:10.1007/s00436-022-07532-5

Cited by 8 publications

(5 citation statements)

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“…The probability distribution function (PDF) analysis revealed that all of the complexes, including the unbound protein, had only one peak, meaning the complexes and the unbound protein were stable with fewer deviations. This corroborates SARS-CoV-2 main protease (M pro ) studies using malaria box compounds as hits [ 102 ] and the screening of inhibitors against Leishmania donovani 3-mercapto pyruvate sulfurtransferase [ 103 ]. The unbound protein, 22,26-azasterol, STOCK6S-84928, and STOCK6S-65920 complexes reached equilibrium with an average RMSD of 0.25 nm ( Supplementary Figure S2a,b ).…”

Section: Resultssupporting

confidence: 75%

“…To determine the effect of loose packing on solvent accessibility, the SASA of the entire protein was computed to provide information on the protein–solvent interactions [ 103 , 105 ]. Generally, high SASA values imply an increase in structural enlargement for the protein–ligand complexes under the influence of solvent surface charges, resulting in a more flexible and unstable conformation [ 105 ].…”

Section: Resultsmentioning

confidence: 99%

“…Generally, high SASA values imply an increase in structural enlargement for the protein–ligand complexes under the influence of solvent surface charges, resulting in a more flexible and unstable conformation [ 105 ]. A complex of L. donovani 3-mercapto pyruvate sulfurtransferase and rutin complex had an average SASA value of 44 nm 2 , which was more compact than the unbound protein with an average SASA of 48 nm 2 [ 103 ]. In the current study, no differences were observed ( Supplementary Figure S5a ) for the unbound protein, the three hits, and 22,26-azasterol complexes.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…In vitro validation has become a popular approach following MDS in recent drug design and discovery processes (Onyango, 2023). Cheng et al (2023), Kant et al (2022), andOrnnork et al (2020) performed in vitro validation of the lead compounds they discovered in their respective studies. Even though they employed different assays in their studies, they had a common goal that this project shares.…”

Section: Discussionmentioning

confidence: 99%

Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Dynamics Simulations of Pfhsp90 Fingerprint Signatures in Plasmodium Malaria Treatment

Onyango,

Gitau,

Muoma

et al. 2024

Preprint

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The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted WHO to recommend prevention strategies like using anti-malarial drugs. However, these strategies have been ineffective because of anti-malarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACTs clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious malaria drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drugs target, this study uses it to discover more efficacious malaria drugs. An in-silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and 9 of them satisfied the requirements. The 9 ZINC compounds were docked with PfHsp90 using the PyRx software to understand their interactions. From the molecular docking results, ZINC09060002 (-8.2 kcal/mol), ZINC72133064 (-7.8 kcal/mol), ZINC72163401 (-7.7 kcal/mol), ZINC72358537 (-8.1 kcal/mol), and ZINC72358557 (-7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (-7.5 kcal/mol). The stability of these molecularly docked protein-inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 – 400 ng/ml. In this regard, the three PfHsp90 inhibitors can be used as anti-malarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

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“…Next, solvent accessible surface area (SASA) was evaluated to determine the efects of the solvent behavior on the stability of the protein-ligand complexes [119,120]. From the SASA graph, it was observed that all the protein-ligand complexes showed similar trajectories with an average SASA value of 115 nm 2 (Figure 8(a)).…”

Section: Molecular Dynamics Simulations Studiesmentioning

confidence: 99%

Docking and Molecular Dynamics Identify Leads against 5 Alpha Reductase 2 for Benign Prostate Hyperplasia Treatment

Saah

Sakyi

Adu-Poku

et al. 2023

Journal of Chemistry

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Steroid 5 alpha-reductase 2 (5αR-2) is a membrane-embedded protein that together with other isoforms plays a key role in the metabolism of steroids. This enzyme catalyzes the reduction of testosterone to the more potent ligand, dihydrotestosterone (DHT) in the prostate. Androgens, testosterone, and DHT play important roles in prostate growth, development, and function. At the same time, both testosterone and DHT have been implicated in the pathogenesis of benign prostate hyperplasia (BPH). Inhibition of the DHT formation, therefore, provides a therapeutic strategy that offers the possibility of preventing, delaying, or treating BPH. Currently, two steroidal drugs that inhibit 5αR-2, dutasteride and finasteride, have been approved for clinical use. These two come at a high cost and also portray undesirable sexual side effects which necessitate the need to find new chemotherapeutic alternatives for the disease. Based on the aforementioned, finasteride and dutasteride were subjected to scaffold hopping, fragment-based de novo design, molecular docking, and molecular dynamics simulations employing databases like ChEMBL, DrugBank, PubChem, ChemSpider, and Zinc15 in the identification of potential hits targeting 5αR-2. Altogether, ten novel compounds targeting 5αR-2 were identified with binding energies lower or comparable to finasteride and dutasteride, the main inhibitors for this target. Molecular docking and molecular dynamics simulations studies identify amino acid residues Glu57, Phe219, Phe223, and Leu224 to be critical for ligand binding and complex stability. The physicochemical and pharmacological profiling suggests the potential of the hit compounds to be drug-like and orally active. Similarly, the quality parameter assessments revealed the hits possess LELP greater than 3 implying their promise as lead-like molecules. The compounds A5, A9, and A10 were, respectively, predicted to treat prostate disorders with Pa (0.188, 0.361, and 0.270) and Pi (0.176, 0.050, and 0.093), while A8 and A9 were found to be associated with BPH treatment with Pa (0.09 and 0.127) and Pi (0.077 and 0.033), respectively. Structural similarity searches via DrugBank identified the drugs faropenem, acemetacin, estradiol valerate, and yohimbine to be useful for BPH treatment suggesting the de novo designed ligands as potential chemotherapeutic agents for treating this disease.

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In silico screening, molecular dynamic simulations, and in vitro activity of selected natural compounds as an inhibitor of Leishmania donovani 3-mercaptopyruvate sulfurtransferase

Cited by 8 publications

References 50 publications

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

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

Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Dynamics Simulations of Pfhsp90 Fingerprint Signatures in Plasmodium Malaria Treatment

Docking and Molecular Dynamics Identify Leads against 5 Alpha Reductase 2 for Benign Prostate Hyperplasia Treatment

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