Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists
Апстракт
Serotonin 5-HT2A receptors (5-HT2AR) are highly expressed in human prefrontal cortex, essential for
learning and cognition [1]. Consequently, antagonists of these receptors are effective in treatment of
various neuropsychiatric disorders, such as depression, insomnia, schizophrenia, anxiety, and
cent progress in molecular modelling studies has led to significant success
in drug discovery using ligand and target-based methods. To design novel potent 5-HT2AR antagonists,
we report a strategy of combining three-dimensional quantitative structure-activity relationship (3DQSAR)
modelling with molecular docking and molecular dynamic (MD) simulation. Based on the
common structural features, data set of 75 compounds was divided into three clusters. Firstly, MD
simulations were carried out for each cluster representative in complex with 5-HT2AR, providing
important molecular level insight into their structure and dynamics. Afterward, to provide more
accurate information about binding ...modes in the active site of the receptor, obtained conformations
were used for docking studies and generation of the virtually bioactive conformations of all studied
ligands. In addition, 3D-QSAR study, utilizing selected conformers, was carried out to gain further
insights into the structural requirements that affect their antagonistic activity. Besides, some
commercially available 5-HT2AR antagonists were examined through in vitro PAMPA essay, as well as
in silico computational methods not only to improve BBB permeability of new designed compounds,
but also to establish promising tool to study their membrane permeability in detail. Overall, these and
future results will provide new methodologies that could be used as guidelines for rational drug design
of novel 5-HT2AR antagonists.
Извор:
2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book, 2020, 10-10Издавач:
- European Research Network on Signal Transduction (ERNEST) CA18133
Финансирање / пројекти:
- Синтеза, квантитативни однос између структуре и дејства, физичко-хемијска карактеризација и анализа фармаколошки активних супстанци (RS-MESTD-Basic Research (BR or ON)-172033)
Институција/група
PharmacyTY - CONF AU - Radan, Milica AU - Ružić, Dušan AU - Antonijević, Mirjana AU - Đikić, Teodora AU - Nikolić, Katarina PY - 2020 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4855 AB - Serotonin 5-HT2A receptors (5-HT2AR) are highly expressed in human prefrontal cortex, essential for learning and cognition [1]. Consequently, antagonists of these receptors are effective in treatment of various neuropsychiatric disorders, such as depression, insomnia, schizophrenia, anxiety, and cent progress in molecular modelling studies has led to significant success in drug discovery using ligand and target-based methods. To design novel potent 5-HT2AR antagonists, we report a strategy of combining three-dimensional quantitative structure-activity relationship (3DQSAR) modelling with molecular docking and molecular dynamic (MD) simulation. Based on the common structural features, data set of 75 compounds was divided into three clusters. Firstly, MD simulations were carried out for each cluster representative in complex with 5-HT2AR, providing important molecular level insight into their structure and dynamics. Afterward, to provide more accurate information about binding modes in the active site of the receptor, obtained conformations were used for docking studies and generation of the virtually bioactive conformations of all studied ligands. In addition, 3D-QSAR study, utilizing selected conformers, was carried out to gain further insights into the structural requirements that affect their antagonistic activity. Besides, some commercially available 5-HT2AR antagonists were examined through in vitro PAMPA essay, as well as in silico computational methods not only to improve BBB permeability of new designed compounds, but also to establish promising tool to study their membrane permeability in detail. Overall, these and future results will provide new methodologies that could be used as guidelines for rational drug design of novel 5-HT2AR antagonists. PB - European Research Network on Signal Transduction (ERNEST) CA18133 C3 - 2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book T1 - Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists SP - 10 EP - 10 UR - https://hdl.handle.net/21.15107/rcub_farfar_4855 ER -
@conference{ author = "Radan, Milica and Ružić, Dušan and Antonijević, Mirjana and Đikić, Teodora and Nikolić, Katarina", year = "2020", abstract = "Serotonin 5-HT2A receptors (5-HT2AR) are highly expressed in human prefrontal cortex, essential for learning and cognition [1]. Consequently, antagonists of these receptors are effective in treatment of various neuropsychiatric disorders, such as depression, insomnia, schizophrenia, anxiety, and cent progress in molecular modelling studies has led to significant success in drug discovery using ligand and target-based methods. To design novel potent 5-HT2AR antagonists, we report a strategy of combining three-dimensional quantitative structure-activity relationship (3DQSAR) modelling with molecular docking and molecular dynamic (MD) simulation. Based on the common structural features, data set of 75 compounds was divided into three clusters. Firstly, MD simulations were carried out for each cluster representative in complex with 5-HT2AR, providing important molecular level insight into their structure and dynamics. Afterward, to provide more accurate information about binding modes in the active site of the receptor, obtained conformations were used for docking studies and generation of the virtually bioactive conformations of all studied ligands. In addition, 3D-QSAR study, utilizing selected conformers, was carried out to gain further insights into the structural requirements that affect their antagonistic activity. Besides, some commercially available 5-HT2AR antagonists were examined through in vitro PAMPA essay, as well as in silico computational methods not only to improve BBB permeability of new designed compounds, but also to establish promising tool to study their membrane permeability in detail. Overall, these and future results will provide new methodologies that could be used as guidelines for rational drug design of novel 5-HT2AR antagonists.", publisher = "European Research Network on Signal Transduction (ERNEST) CA18133", journal = "2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book", title = "Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists", pages = "10-10", url = "https://hdl.handle.net/21.15107/rcub_farfar_4855" }
Radan, M., Ružić, D., Antonijević, M., Đikić, T.,& Nikolić, K.. (2020). Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists. in 2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book European Research Network on Signal Transduction (ERNEST) CA18133., 10-10. https://hdl.handle.net/21.15107/rcub_farfar_4855
Radan M, Ružić D, Antonijević M, Đikić T, Nikolić K. Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists. in 2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book. 2020;:10-10. https://hdl.handle.net/21.15107/rcub_farfar_4855 .
Radan, Milica, Ružić, Dušan, Antonijević, Mirjana, Đikić, Teodora, Nikolić, Katarina, "Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists" in 2nd ERNEST Online Meeting New Perspectives in Signal Transduction: GPCRs and Beyond, 28-30 March 2020, Abstract Book (2020):10-10, https://hdl.handle.net/21.15107/rcub_farfar_4855 .