Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

Śliwa, Paweł; Kurczab, Rafał; Kafel, Rafał; Drabczyk, Anna K.; Jaśkowska, Jolanta

doi:10.1007/s00894-019-3995-6

Cited by 12 publications

(10 citation statements)

References 54 publications

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“…In the case of serotonin 5-HT 7 receptor, first, we constructed a homology model of this protein. Our model is an addition to previously published homology models of serotonin 5-HT 7 receptor [46][47][48][49] and is in general accordance with them. Molecular interactions of D2AAK4 with the studied aminergic GPCRs are typical for ligands with a protonatable nitrogen atom interacting with the conserved Asp 3.32 as the main anchoring point [50].…”

Section: Discussionsupporting

confidence: 81%

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

et al. 2020

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N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity.

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Section: Discussionsupporting

confidence: 81%

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

et al. 2020

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“…PIE value consists of the following contributions to total energy: E es —electrostatic, E ex —exchange repulsion, E ct —charge-transfer, E disp —dispersion, E solv —the Gibbs solvation energy. The index %E es+ct describing how much polar an interaction is was calculated following the proposition by Śliwa et al [ 93 ], according to the equation:

…”

Section: Methodsmentioning

confidence: 99%

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

Matalińska

Lipiński

Kossoń

et al. 2020

IJMS

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AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

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“…FMO method was described by Kato et al and Sliwa et al 28,29 . In summary, on the NDM and CPH and BJP proteins, protonate 3D, N-and C-termini capping and energy minimization with AMBER10: EHT force field was done via MOE program.…”

Section: Docking With Biapenem Three Typical Patterns Of Mbl Classesmentioning

confidence: 99%

Discovery of potential inhibitors against New Delhi metallo-β-lactamase-1 from natural compounds: in silico-based methods

Salari-Jazi

Mahnam

Sadeghi

et al. 2021

Sci Rep

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New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-β-lactamases in experimental studies.

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Recognition of repulsive and attractive regions of selected serotonin receptor binding site using FMO-EDA approach

Cited by 12 publications

References 54 publications

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

Discovery of potential inhibitors against New Delhi metallo-β-lactamase-1 from natural compounds: in silico-based methods

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