BRUSELAS: HPC Generic and Customizable Software Architecture for 3D Ligand-Based Virtual Screening of Large Molecular Databases

Banegas-Luna, Antonio Jesús; Cerón‐Carrasco, José P.; Puertas-Martín, Savíns; Pérez‐Sánchez, Horacio

doi:10.1021/acs.jcim.9b00279

Cited by 16 publications

(15 citation statements)

References 63 publications

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“…Thus, siderol has great potential to be exploited as a potent anticancer agent, and its derivatization or formulation should be considered in order to enhance even more its cytotoxic efficacy. In order to evaluate the potential similarity of the isolated chemotype of siderol with other compounds with known bioactivity in the CHEMBL database, we conducted a 3D-based virtual screening [36]. The highest hits, going from the highest-ranking to the lowest, were compounds (4aS,6S,6aS,8S,9R,11aS,11bS)-8-hydroxy-4,4,9,11b-tetramethyltetradecahydro-9,11a-methanocyclohepta [a]naphthalen-6-yl acetate (CHEMBL494391), (4aS,4bR,8R,8aR,9R,10aR)-8-(hydroxymethyl)-1,4b,8trimethyl-2-vinyl-3,4,4a,4b,5,6,7,8,8a,9,10,10a-dodecahydrophenanthren-9-yl acetate (CHEMBL482794), (4aR,5S,6aS,7R,9R,11bR)-5-hydroxy-4,4,11b-trimethyl-8-methylene-1,2,3,4,4a,5,6,7,8,9,10,11b-dodecahydro-6a,9-methanocyclohepta[a]naphthalen-7-yl acetate (CHEMBL448113), ((1R,4aS,4bR,7S,8aS,10aR)-8a-hydroxy-1,4a,7-trimethyl-7-vinyltetradecahydrophenanthren-1-yl)methyl acetate (CHEMBL509521), and ethyl (4R,4aS,6aR,9S,11aR,11bS)-4,9,11b-trimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[a] naphthalene-4-carboxylate (CHEMBL455441).…”

Section: Resultsmentioning

confidence: 99%

NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr.

et al. 2020

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Diterpenes are characteristic compounds from the genus Sideritis L., possessing an array of biological activities. Siderol is the main constituent of the ent-kaurene diterpenes in Sideritis species. In order to isolate the specific compound and evaluate for the first time its cytotoxic activity, we explored the dichloromethane extract of cultivated Sideritis euboea Heldr. To track the specific natural bioactive agent, we applied NMR spectroscopy to the crude plant extract, since NMR can serve as a powerful and rapid tool both to navigate the targeted isolation process of bioactive constituents, and to also reveal the identity of bioactive components. Along these lines, from the rapid 1D 1H NMR spectrum of the total crude plant extract, we were able to determine the characteristic proton NMR signals of siderol. Furthermore, with the same NMR spectrum, we were able to categorize several secondary metabolites into chemical groups as a control of the isolation process. Therefore, this non-polar extract was explored, for the first time, revealing eleven compounds—one fatty acid ester; 2-(p-hydroxyphenyl)ethylstearate (1), three phytosterols; β-sitosterol (2), stigmasterol (3), and campesterol (4); one triterpenoid; ursolic acid (5), four diterpenoids; siderol (6), eubol (7), eubotriol (8), 7-epicandicandiol (9) and two flavonoids; xanthomicrol (10) and penduletin (11). The main isolated constituent was siderol. The antiproliferative potential of siderol was evaluated, using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, on three human cancer cell lines DLD1, HeLa, and A549, where the IC50 values were estimated at 26.4 ± 3.7, 44.7 ± 7.2, and 46.0 ± 4.9 μΜ, respectively. The most potent activity was recorded in the human colon cancer cell line DLD1, where siderol exhibited the lowest IC50. Our study unveiled the beneficial potential of siderol as a remarkable cytotoxic agent and the significant contribution of NMR spectroscopy towards the isolation and identification of this potent anticancer agent.

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Section: Resultsmentioning

confidence: 99%

NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr.

et al. 2020

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“…A workflow schema detailing the stepwise techniques employed in this study is shown in Figure 1 . The compound 22,26-azaserol was submitted to balanced rapid and unrestricted server for extensive ligand-aimed screening (BRUSELAS) ( Banegas-Luna et al., 2019 ) to generate non-steroidal inhibitors. Meanwhile, a reasonably good structure of Ld SMT was modeled and validated.…”

Section: Methodsmentioning

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 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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“…For a more comprehensive explanation of the software and the obtained results, reading the original works (Puertas-Martín et al, 2019;Puertas-Martín et al, 2020) is recommended. It is also available in the free-to-use server BRUSELAS (Banegas-Luna et al, 2019).…”

Section: Software Configurationmentioning

confidence: 99%

MultiPharm-DT: A Multi-Objective Decision Tool for Ligand-Based Virtual Screening Problems

Puertas-Martín¹,

Redondo²,

Ferrández³

et al. 2021

Informatica

Self Cite

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Ligand Based Virtual Screening methods are used to screen molecule databases to select the most promising compounds for a query. This is performed by decision-makers based on the information of the descriptors, which are usually processed individually. This methodology leads to a lack of information and hard post-processing dependent on the expert's knowledge that can end up in the discarding of promising compounds. Consequently, in this work, we propose a new multi-objective methodology called MultiPharm-DT where several descriptors are considered simultaneously and whose results are offered to the decision-maker without effort on their part and without relying on their expertise.

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BRUSELAS: HPC Generic and Customizable Software Architecture for 3D Ligand-Based Virtual Screening of Large Molecular Databases

Cited by 16 publications

References 63 publications

NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr.

NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr.

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

MultiPharm-DT: A Multi-Objective Decision Tool for Ligand-Based Virtual Screening Problems

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