Potential modulating effect of the Ascaris suum nicotinic acetylcholine receptor (nAChR) by compounds GSK575594A, diazepam and flumazenil discovered by structure-based virtual screening approach
Samo za registrovane korisnike
2021
Autori
Stevanović, StrahinjaMarjanović, Đorđe
Trailović, Saša
Zdravković, Nemanja
Perdih, Andrej
Nikolić, Katarina
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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 μM) increased the Emax by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 μM) decreased the Emax 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 μM to 4.88 μM) value showing dose ratio of 2.30, and increased the Emax 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.
Ključne reči:
Antihelmintic compounds / Ascaris suum / Contraction assays / GSK575594A / Homology modelling / Ligand-based pharmacophore modelling / Molecular docking, virtual screening / Parasite nAChRIzvor:
Molecular and Biochemical Parasitology, 2021, 242Izdavač:
- Elsevier B.V.
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200161 (Univerzitet u Beogradu, Farmaceutski fakultet) (RS-MESTD-inst-2020-200161)
- Razvoj biljnih lekova i biocida na bazi karvakrola, timola i cinamaldehida za primenu u veterinarskoj medicini, stočarstvu i proizvodnji hrane bez štetnih rezidua (RS-MESTD-Technological Development (TD or TR)-31087)
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200143 (Univerzitet u Beogradu, Fakultet veterinarske medicine) (RS-MESTD-inst-2020-200143)
- Ministry of Higher Education, Science and Technology of the Republic of Slovenia through Research Program Grant P1-0012
DOI: 10.1016/j.molbiopara.2021.111350
ISSN: 0166-6851
WoS: 000723158800002
Scopus: 2-s2.0-85099167432
Institucija/grupa
PharmacyTY - JOUR AU - Stevanović, Strahinja AU - Marjanović, Đorđe AU - Trailović, Saša AU - Zdravković, Nemanja AU - Perdih, Andrej AU - Nikolić, Katarina PY - 2021 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3766 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 μM) increased the Emax by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 μM) decreased the Emax 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 μM to 4.88 μM) value showing dose ratio of 2.30, and increased the Emax 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 - Elsevier B.V. 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 ER -
@article{ author = "Stevanović, Strahinja and Marjanović, Đorđe 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 μM) increased the Emax by 21 % with the EC50 dose ratio of 0.96. Diazepam (100 μM) decreased the Emax 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 μM to 4.88 μM) value showing dose ratio of 2.30, and increased the Emax 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 = "Elsevier B.V.", 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" }
Stevanović, S., Marjanović, Đ., 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 Elsevier B.V.., 242. https://doi.org/10.1016/j.molbiopara.2021.111350
Stevanović S, Marjanović Đ, 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 .
Stevanović, Strahinja, Marjanović, Đorđe, 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 . .