LiSiCA: A Software for Ligand-Based Virtual Screening and Its Application for the Discovery of Butyrylcholinesterase Inhibitors

Lešnik, Samo; Štular, Tanja; Brus, Boris; Knez, Damijan; Gobec, Stanislav; Janežič, Dušanka; Konc, Janez

doi:10.1021/acs.jcim.5b00136

Cited by 77 publications

(52 citation statements)

References 35 publications

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“…Retinol acetate was used as the reference compound for similarity searching in a database that comprises a total of 2924 worldwide commercially available drugs and nutraceuticals approved by U.S. Food and Drug Administration (FDA). This screening was performed using LiSiCA v1.0 (Ligand Similarity using Clique Algorithm) software [32], and similarities were expressed using the Tanimoto coefficient [33]. The structural data of compounds retrieved from similarity screening, as well as putrescine and spermidine, Tc PAT12 natural ligands.…”

Section: Methodsmentioning

confidence: 99%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

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Section: Methodsmentioning

confidence: 99%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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“…A definite confirmation of the usefulness of this method will come from experimental studies, which are planned in the future. It is also our plan to implement this method in LiSiCA, [24] our ligand-based virtual screening software, to enable searching large databases for similar ligands not only on the basis of atom type similarity but also based on possible bioisosteric or scaffold hopping replacements.…”

Section: Resultsmentioning

confidence: 99%

Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Lešnik¹,

Konc²,

Janežič³

2016

Croat. Chem. Acta

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Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate -a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor.

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“…With LiSiCA we obtained an average area under the ROC curve of 0.71 ± 0.15 and 0.67 ± 0.16, for 2D and 3D screening respectively, whereas with ShaEP we obtained an average of 0.57 ± 0.11, which is significantly lower compared to the results of both the LiSiCA’s screening options. We also employed LiSiCA for the discovery of new nanomolar butyrylcholinesterase inhibitors [14]; we used the bioactive conformation of a known inhibitor (PDB code: 3F9) [19] obtained from the butyrylcholinesterase enzyme (PDB ID: 4TPK) as a reference molecule and screened it against the ZINC Drugs Now database using the LiSiCA’s 3D option. To cover as much conformational space as possible, we initially prepared on average 188 conformers per each database compound.…”

Section: Resultsmentioning

confidence: 99%

“…The developed plugin represents an interface between PyMOL and LiSiCA, an LBVS software based on a graph theoretical maximum clique algorithm (http://insilab.org/maxclique) [13, 14]. The main purpose of this interface is to enable visualization of large amounts of data returned from LiSiCA’s output within the preferred environment of many researchers.…”

Section: Introductionmentioning

confidence: 99%

Ligand-based virtual screening interface between PyMOL and LiSiCA

et al. 2016

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Ligand-based virtual screening of large small-molecule databases is an important step in the early stages of drug development. It is based on the similarity principle and is used to reduce the chemical space of large databases to a manageable size where chosen ligands can be experimentally tested. Ligand-based virtual screening can also be used to identify bioactive molecules with different basic scaffolds compared to already known bioactive molecules, thus having the potential to increase the structural variability of compounds. Here, we present an interface between the popular molecular graphics system PyMOL and the ligand-based virtual screening software LiSiCA available at http://insilab.org/lisica-plugin and demonstrate how this interface can be used in the early stages of drug discovery process.Graphical AbstractLigand-based virtual screening interface between PyMOL and LiSiCA.

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LiSiCA: A Software for Ligand-Based Virtual Screening and Its Application for the Discovery of Butyrylcholinesterase Inhibitors

Cited by 77 publications

References 35 publications

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Ligand-based virtual screening interface between PyMOL and LiSiCA

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