Abstract
The emergence of antibiotic-resistant pathogens generates impairment to human health. U1-SCTRX-lg1a is a peptide isolated from a phospholipase D extracted from the spider venom of Loxosceles gaucho with antimicrobial activity against Gram-negative bacteria (between 1.15 and 4.6 μM). The aim of this study was to suggest potential receptors associated with the antimicrobial activity of U1-SCTRX-lg1a using in silico bioinformatics tools. The search for potential targets of U1-SCRTX-lg1a was performed using the PharmMapper server. Molecular docking between U1-SCRTX-lg1a and the receptor was performed using PatchDock software. The prediction of ligand sites for each receptor was conducted using the PDBSum server. Chimera 1.6 software was used to perform molecular dynamics simulations only for the best dock score receptor. In addition, U1-SCRTX-lg1a and native ligand interactions were compared using AutoDock Vina software. Finally, predicted interactions were compared with the ligand site previously described in the literature. The bioprospecting of U1-SCRTX-lg1a resulted in the identification of three hundred (300) diverse targets (Table S1), forty-nine (49) of which were intracellular proteins originating from Gram-negative microorganisms (Table S2). Docking results indicate Scores (10,702 to 6066), Areas (1498.70 to 728.40) and ACEs (417.90 to – 152.8) values. Among these, NAD + NH3-dependent synthetase (PDB ID: 1wxi) showed a dock score of 9742, area of 1223.6 and ACE of 38.38 in addition to presenting a Normalized Fit score of 8812 on PharmMapper server. Analysis of the interaction of ligands and receptors suggests that the peptide derived from brown spider venom can interact with residues SER48 and THR160. Furthermore, the C terminus (– 7.0 score) has greater affinity for the receptor than the N terminus (– 7.7 score). The molecular dynamics assay shown that free energy value for the protein complex of – 214,890.21 kJ/mol, whereas with rigid docking, this value was – 29.952.8 sugerindo that after the molecular dynamics simulation, the complex exhibits a more favorable energy value compared to the previous state. The in silico bioprospecting of receptors suggests that U1-SCRTX-lg1a may interfere with NAD + production in Escherichia coli, a Gram-negative bacterium, altering the homeostasis of the microorganism and impairing growth.
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Data and software availability
The physicochemical properties were determined via the Heliquest server https://heliquest.ipmc.cnrs.fr/. Potential receptors were screened through PharmMapper available in http://www.lilab-ecust.cn/pharmmapper/. Sequence and files of receptors were downloaded from website protein data bank https://www.rcsb.org/. A molecular docking method was used: PatchDock https://bioinfo3d.cs.tau.ac.il/PatchDock/ and https://vina.scripps.edu/. Ligand and receptor interaction, molecular presentation was built by free software UCSF chimera (version 1.16) https://www.cgl.ucsf.edu/chimera/. For prediction of ligand site, it was used by the PDBsum server http://www.ebi.ac.uk/thornton-srv/databases/pdbsum/. All files used in this study are available in https://github.com/loxoscelesgaucho/loxosceles-in-silico.git.
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Acknowledgements
We thank all the team of the Protein Chemistry Laboratory at the Laboratory from Applied Toxinology (LETA—Butantan Institute, Brazil) for the constant support and encouragement.
Funding
This research received financial support from the Research Support Foundation of the State of São Paulo (FAPESP/CeTICS), grant number 2013/07467–1, Brazilian National Council for Scientific and Technological Development (CNPq), grant numbers 472744/2012–7 and 161722/2021–0, and from Higher Education Personnel Improvement Coordination (CAPES) process number 88887.663437/2022–00.
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Names in alphabetical order. Conceptualization and methodology: ASO, EJMS and P.I.S.Jr.; validation, formal analysis, investigation, resources, and data curation:ASO, EJMS and P.I.S.Jr; writing original draft: ASO and EJMS; review and editing, and visualization: ASO and EJMS and P.I.S.Jr.; supervision: P.I.S.Jr.; project administration and funding acquisition: P.I.S.Jr. All authors have read and agreed to the published version of the manuscript.
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de Oliveira, A.S., Muniz Seif, E.J. & da Silva Junior, P.I. In silico prospection of receptors associated with the biological activity of U1-SCTRX-lg1a: an antimicrobial peptide isolated from the venom of Loxosceles gaucho. In Silico Pharmacol. 12, 15 (2024). https://doi.org/10.1007/s40203-024-00190-8
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DOI: https://doi.org/10.1007/s40203-024-00190-8