Application of Fragment Molecular Orbital Method to investigate dopamine receptors

Preikša, Jokūbas; Śliwa, Paweł

doi:10.5604/01.3001.0013.5526

Cited by 2 publications

(2 citation statements)

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“…Interestingly, this correlates very well with the low values of the crystal temperature factors (B-factor) for atoms involved in the XB. In summary, the halogen bond with V5x40 is an important factor determining the binding mode of nemonapride with D 4 R. Moreover, the significance of this interaction was recently indicated based on the ab initio FMO calculation in combination with PIEDA analysis [34]. The study showed that XB between V5x40 and nemonapride is mostly dispersion-dependent, which was additional evidence of the hydrophobic nature of XBs.…”

Section: The 5wiu: MD Simulation Of the D 4 Receptor In Complex With mentioning

confidence: 83%

The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

2019

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Recently, a computational approach combining a structure–activity relationship library containing pairs of halogenated ligands and their corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking and binding free energy calculations was developed and used to search for amino acids frequently targeted by halogen bonding, also known as XB hot spots. However, the analysis of ligand–receptor complexes with halogen bonds obtained by molecular docking provides a limited ability to study the role and significance of halogen bonding in biological systems. Thus, a set of molecular dynamics simulations for the dopamine D4 receptor, recently crystallized with the antipsychotic drug nemonapride (5WIU), and the five XSAR sets were performed to verify the identified hot spots for halogen bonding, in other words, primary (V5x40), and secondary (S5x43, S5x461 and H6x55). The simulations confirmed the key role of halogen bonding with V5x40 and H6x55 and supported S5x43 and S5x461. The results showed that steric restrictions and the topology of the molecular core have a crucial impact on the stabilization of the ligand–receptor complex by halogen bonding.

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Section: The 5wiu: MD Simulation Of the D 4 Receptor In Complex With mentioning

confidence: 83%

The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

2019

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“…In FMO/PIEDA biomolecules, such proteins or nucleic acids are divided into substructures (fragments) and pair interaction energies (PIE) are calculated for such resulting individual fragments, making calculations more accurate than for whole large molecules [24][25][26]. The computational scheme proposed in this paper has been successfully applied previously to theoretical considerations of GPCR-targeted new drug design [27][28][29][30][31] as well as to deep insight into structure-activity relationship (SAR) analysis [32,33]. However, such a computationally comprehensive approach presented within this study has not been employed yet for D4R and the design of its ligands.…”

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confidence: 99%

The Pivotal Distinction between Antagonists’ and Agonists’ Binding into Dopamine D4 Receptor—MD and FMO/PIEDA Studies

Śliwa,

Dziurzyńska,

Kurczab

et al. 2024

IJMS

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The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L–R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.

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Application of Fragment Molecular Orbital Method to investigate dopamine receptors

Cited by 2 publications

References 50 publications

The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

The Significance of Halogen Bonding in Ligand–Receptor Interactions: The Lesson Learned from Molecular Dynamic Simulations of the D4 Receptor

The Pivotal Distinction between Antagonists’ and Agonists’ Binding into Dopamine D4 Receptor—MD and FMO/PIEDA Studies

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