Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach
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2021
Authors
Stevanović, StrahinjaMarjanović, Đorđe S.
Trailović, Saša
Zdravković, Nemanja
Perdih, Andrej
Nikolić, Katarina
Article (Published version)
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Parasitic infections are a widespread health problem and research of novel anthelmintic compounds is of the utmost importance. In this study we performed a virtual screening campaign by coupling ligand-based pharmacophore, homology modeling and molecular docking. The virtual screening campaign was conducted using a joined pool of the Drugbank database and a library of purchasable compounds in order to identify drug like compounds with similar pharmacological activity. Our aim was to identify compounds with a potential antihelmintic modulatory effect on nicotinic acetylcholine receptors (nAChR). We derived a 3D pharmacophore model based on the chemical features of known Ascaris suum nAChR modulators. To evaluate the in silico predictions, we tested selected hit compounds in contraction assays using somatic muscle flaps of the Ascaris suum neuromuscular tissue. We tested the modulatory effects of GSK575594A, diazepam and flumazenil hit compounds on nematode contractions induced by acetyl... choline (ACh). The compound GSK575594A (3 mu M) increased the E-max by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 mu M) decreased the E-max by 15 % (1.11 g to 0.95 g) with the EC50 ratio of 1.42 (shifted to the left from 11.25 to 7.93). Flumazenil decreased the EC50 value (from 11.22 mu M to 4.88 mu M) value showing dose ratio of 2.30, and increased the E-max by 4 % (from 1.54 g to 1.59 g). The observed biological activity was rationalized by molecular docking calculations. Docking scores were calculated against several binding sites within the Ascaris suum homology model. We constructed the homology model using the ACR-16 subunit sequence. The compound GSK575594A showed strong affinity for the intersubunit allosteric binding site within the nAChR transmembrane domain. The binding modes of diazepam and flumazenil suggest that these compounds have a comparable affinity for orthosteric and allosteric nAChR binding sites. The selected hit compounds displayed potential for further optimization as lead compounds. Therefore, such compounds may be useful in neutralizing the growing resistance of parasites to drugs, either alone or in combination with existing conventional anthelmintics.
Keywords:
Parasite nAChR / Molecular docking, virtual screening / Ligand-based pharmacophore modelling / Homology modelling / GSK575594A / Contraction assays / Ascaris suum / Antihelmintic compoundsSource:
Molecular and Biochemical Parasitology, 2021, 242Publisher:
- Amsterdam : Elsevier
Funding / projects:
- Development of herbal medicines and biocides on the basis of Carvacrol, Thymol and Cinnamaldehyde for use in veterinary medicine, animal husbandry and food production without harmful residues (RS-MESTD-Technological Development (TD or TR)-31087)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200161 (University of Belgrade, Faculty of Pharmacy) (RS-MESTD-inst-2020-200161)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200143 (University of Belgrade, Faculty of Veterinary Medicine) (RS-MESTD-inst-2020-200143)
DOI: 10.1016/j.molbiopara.2021.111350
ISSN: 0166-6851
PubMed: 33422580
WoS: 000723158800002
Scopus: 2-s2.0-85099167432
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Naučni institut za veterinarstvo SrbijeTY - JOUR AU - Stevanović, Strahinja AU - Marjanović, Đorđe S. AU - Trailović, Saša AU - Zdravković, Nemanja AU - Perdih, Andrej AU - Nikolić, Katarina PY - 2021 UR - https://reponivs.nivs.rs/handle/123456789/450 AB - Parasitic infections are a widespread health problem and research of novel anthelmintic compounds is of the utmost importance. In this study we performed a virtual screening campaign by coupling ligand-based pharmacophore, homology modeling and molecular docking. The virtual screening campaign was conducted using a joined pool of the Drugbank database and a library of purchasable compounds in order to identify drug like compounds with similar pharmacological activity. Our aim was to identify compounds with a potential antihelmintic modulatory effect on nicotinic acetylcholine receptors (nAChR). We derived a 3D pharmacophore model based on the chemical features of known Ascaris suum nAChR modulators. To evaluate the in silico predictions, we tested selected hit compounds in contraction assays using somatic muscle flaps of the Ascaris suum neuromuscular tissue. We tested the modulatory effects of GSK575594A, diazepam and flumazenil hit compounds on nematode contractions induced by acetyl choline (ACh). The compound GSK575594A (3 mu M) increased the E-max by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 mu M) decreased the E-max by 15 % (1.11 g to 0.95 g) with the EC50 ratio of 1.42 (shifted to the left from 11.25 to 7.93). Flumazenil decreased the EC50 value (from 11.22 mu M to 4.88 mu M) value showing dose ratio of 2.30, and increased the E-max by 4 % (from 1.54 g to 1.59 g). The observed biological activity was rationalized by molecular docking calculations. Docking scores were calculated against several binding sites within the Ascaris suum homology model. We constructed the homology model using the ACR-16 subunit sequence. The compound GSK575594A showed strong affinity for the intersubunit allosteric binding site within the nAChR transmembrane domain. The binding modes of diazepam and flumazenil suggest that these compounds have a comparable affinity for orthosteric and allosteric nAChR binding sites. The selected hit compounds displayed potential for further optimization as lead compounds. Therefore, such compounds may be useful in neutralizing the growing resistance of parasites to drugs, either alone or in combination with existing conventional anthelmintics. PB - Amsterdam : Elsevier T2 - Molecular and Biochemical Parasitology T1 - Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach VL - 242 DO - 10.1016/j.molbiopara.2021.111350 UR - conv_576 ER -
@article{ author = "Stevanović, Strahinja and Marjanović, Đorđe S. and Trailović, Saša and Zdravković, Nemanja and Perdih, Andrej and Nikolić, Katarina", year = "2021", abstract = "Parasitic infections are a widespread health problem and research of novel anthelmintic compounds is of the utmost importance. In this study we performed a virtual screening campaign by coupling ligand-based pharmacophore, homology modeling and molecular docking. The virtual screening campaign was conducted using a joined pool of the Drugbank database and a library of purchasable compounds in order to identify drug like compounds with similar pharmacological activity. Our aim was to identify compounds with a potential antihelmintic modulatory effect on nicotinic acetylcholine receptors (nAChR). We derived a 3D pharmacophore model based on the chemical features of known Ascaris suum nAChR modulators. To evaluate the in silico predictions, we tested selected hit compounds in contraction assays using somatic muscle flaps of the Ascaris suum neuromuscular tissue. We tested the modulatory effects of GSK575594A, diazepam and flumazenil hit compounds on nematode contractions induced by acetyl choline (ACh). The compound GSK575594A (3 mu M) increased the E-max by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 mu M) decreased the E-max by 15 % (1.11 g to 0.95 g) with the EC50 ratio of 1.42 (shifted to the left from 11.25 to 7.93). Flumazenil decreased the EC50 value (from 11.22 mu M to 4.88 mu M) value showing dose ratio of 2.30, and increased the E-max by 4 % (from 1.54 g to 1.59 g). The observed biological activity was rationalized by molecular docking calculations. Docking scores were calculated against several binding sites within the Ascaris suum homology model. We constructed the homology model using the ACR-16 subunit sequence. The compound GSK575594A showed strong affinity for the intersubunit allosteric binding site within the nAChR transmembrane domain. The binding modes of diazepam and flumazenil suggest that these compounds have a comparable affinity for orthosteric and allosteric nAChR binding sites. The selected hit compounds displayed potential for further optimization as lead compounds. Therefore, such compounds may be useful in neutralizing the growing resistance of parasites to drugs, either alone or in combination with existing conventional anthelmintics.", publisher = "Amsterdam : Elsevier", journal = "Molecular and Biochemical Parasitology", title = "Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach", volume = "242", doi = "10.1016/j.molbiopara.2021.111350", url = "conv_576" }
Stevanović, S., Marjanović, Đ. S., Trailović, S., Zdravković, N., Perdih, A.,& Nikolić, K.. (2021). Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach. in Molecular and Biochemical Parasitology Amsterdam : Elsevier., 242. https://doi.org/10.1016/j.molbiopara.2021.111350 conv_576
Stevanović S, Marjanović ĐS, Trailović S, Zdravković N, Perdih A, Nikolić K. Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach. in Molecular and Biochemical Parasitology. 2021;242. doi:10.1016/j.molbiopara.2021.111350 conv_576 .
Stevanović, Strahinja, Marjanović, Đorđe S., Trailović, Saša, Zdravković, Nemanja, Perdih, Andrej, Nikolić, Katarina, "Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach" in Molecular and Biochemical Parasitology, 242 (2021), https://doi.org/10.1016/j.molbiopara.2021.111350 ., conv_576 .