New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies

Farid, Ramy; Day, Tyler; Friesner, Richard A.; Pearlstein, Robert A.

doi:10.1016/j.bmc.2005.12.032

Cited by 439 publications

(393 citation statements)

References 39 publications

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“…Because 2 has a cLogP of 4.08, we reasoned that the moderate hERG binding activity of 2 could be ascribed to the hydrophobicity KEYWORDS: CCR2, chemokine, antagonist, hERG, oral absorption of the molecule. While the impact on CCR2 binding could not be predicted, if the cLogP is decreased, it is likely that the hERG activity could be reduced, 11,12 The high cLogP of 2 is attributed to the two hydrophobic phenyl rings on the left-hand and righthand sides. Our previous SAR studies had demonstrated that the trifluoromethylphenyl residue on the right-hand side is critical to the CCR2 binding affinity.…”

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confidence: 99%

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

Xue

Feng

Cao

et al. 2011

ACS Med. Chem. Lett.

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b S Supporting Information M acrophages, which are derived from monocytes, a subset of leukocytes, are well-characterized mediators of tissue destruction. These cells can be activated to secrete proinflammatory cytokines such as TNFR and IL-1β, tissue-degrading enzymes such as MMPs, and other chemokines that mediate the influx of other inflammatory cells. 1 Excessive recruitment of these cells to sites of inflammation leads to significant tissue destruction and contributes to the morbidity of chronic inflammatory and autoimmune diseases. The trafficking of monocytes/ macrophages to sites of inflammation is believed to be predominantly mediated by monocyte chemoattractant protein-1 (MCP-1, CCL2) through interaction with its specific receptor, CCR2, which is a member of the super family of seven-transmembrane G-protein-coupled receptors (GPCRs) and is predominantly expressed on monocytes. Binding of MCP-1 to CCR2 induces chemotaxis, resulting in directed migration of monocytes/macrophages to disease sites where MCP-1 expression is elevated. 2 Studies in rodent models have demonstrated the critical role of MCP-1/CCR2 in inflammatory and autoimmune diseases and strongly suggest that CCR2 is an attractive therapeutic target. 3 As a result, inhibition of CCR2 has emerged as a novel therapeutic approach for pharmaceutical research, and a number of potent small molecule CCR2 antagonists have been identified. 4À10 We have reported the discovery of a novel series of CCR2 antagonists through rational design. 10 Our structureÀactivity relationship (SAR) studies on that series of compounds led to the identification of INCB3344 (Figure 1), a potent, selective, and orally bioavailable antagonist of human and murine CCR2 (hCCR2 and mCCR2). INCB3344 has been used as a tool compound for target validation in rodent models because of its potent inhibitory activity toward murine CCR2, its selectivity over other homologous chemokine receptors, and its good pharmacokinetics profile but was not suitable as a clinical candidate due to its moderate hERG activity (IC 50 = 13 μM) as assessed using a dofetilide binding assay, which did not meet our criteria in hERG binding activity. In addition, INCB3344 was an inhibitor of CYP3A4.In the course of SAR studies on the INCB3344 series in an attempt to identify a clinical candidate, we discovered that removal of the ethoxy at the 3-position on the pyrrolidine in the INCB3344 series as in 1 (Figure 2) resulted in a significant loss in mCCR2 activity but retained the hCCR2 activity as in 2 (Figure 2). An R configuration at the 3-position on the pyrrolidine as shown in 2 is required for activity as the S enantiomer of 2 displayed an IC 50 of >1 μM in hCCR2 MCP-1 assay. Although this des-ethoxy series is not superior to the INCB3344 series by comparison of 2 with 1 in hCCR2 activity and hERG binding activity, the 1,3-disubstituted pyrrolidine core in this series offers an advantage over the 1,3,4-trisubstituted pyrrolidine core in the INCB3344 series from a synthetic point of view as the former ...

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confidence: 99%

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

Xue

Feng

Cao

et al. 2011

ACS Med. Chem. Lett.

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“…An alternative would be to take into account the target protein. A structure-based screening method with homology models of the ion conduction unit of hERG to predict inhibitory activity of compounds is discussed below [47][48][49][50][51][52].…”

Section: Issues and Resolutionsmentioning

confidence: 99%

“…So although hERG possesses large N and C termini [2,89], the crystal structure of a K + channel with an open pore is a suitable reference structure to generate the 3D model of an ion conduction unit of hERG [47,48,50,[90][91][92]]. …”

Section: A Inanobe Et Almentioning

confidence: 99%

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In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

et al. 2008

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A variety of compounds with different chemical properties directly interact with the cardiac repolarizing K + channel encoded by the human ether-a-go-go-related gene (hERG). This causes acquired forms of QT prolongation, which can result in lethal cardiac arrhythmias, including torsades de pointes one of the most serious adverse effects of various therapeutic agents. Prediction of this phenomenon will improve the safety of pharmacological therapy and also facilitate the process of drug development. Here we propose a strategy for the development of an in silico system to predict the potency of chemical compounds to block hERG. The system consists of two sequential processes. The first process is a ligand-based prediction to estimate half-maximal concentrations for the block of compounds inhibiting hERG current using the relationship between chemical features and activities of compounds. The second process is a protein-based prediction that comprises homology modeling of hERG, docking simulation of chemical-channel interaction, analysis of the shape of the channel pore cavity, and Brownian dynamics simulation to estimate hERG currents in the presence and absence of chemical blockers. Since each process is a combination of various calculations, the criterion for assessment at each calculation and the strategy to integrate these steps are significant for the construction of the system to predict a chemical's block of hERG current and also to predict the risk of inducing cardiac arrhythmias from the chemical information. The principles and criteria of elemental computations along this strategy are described.Key words: hERG, quantitative structure-activity relationship, molecular docking, Brownian dynamics simulation.Many ion channels and ion transporting systems contribute to the generation of the action potential of the heart. The ventricular action potential possesses a longlasting plateau that is terminated by the activation of repolarizing K + currents, I Kr and I Ks . The disturbance of these currents causes prolongation of the action potential duration and thus the QT interval of the electrocardiogram, and in many cases a worsening of transmural dispersion of repolarization [1][2][3]. These are the substrates for generation of life-threatening cardiac arrhythmias, including torsades de pointes. Many compounds inhibit I Kr , whose pore-forming subunit is the human ether-a-gogo-related gene (hERG) product. This can cause acquired forms of long QT syndrome [4][5][6]. The compounds exhibit a broad spectrum, including not only cardiac ion channel blockers, but also antipsychotic agents, antidepressant agents, antimicrobial agents, phosphodiesterase inhibitors, topoisomerase II inhibitors, and antagonists for G protein-coupled receptors, such as nonsedating antihistamine H 1 receptor blockers and β blockers [6]. The development of methods that could predict this phenomenon would improve the safety of pharmacological therapy and also facilitate the process of drug development.Here we propose an in silico str...

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“…The active site was defined by the centroid rendered from inhibitor observed in crystallographic structure. For top-10 docking poses generated by Glide/ XP, a multi-stage induced fit docking (IFD) method was also performed 33 . For IFD, the van der Waals radius rendering for the complex was set by a factor of 0.5 and ligands were docked with the default Glide/SP.…”

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confidence: 99%

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

Salmas

Ünlü

Yurtsever

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.

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New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies

Cited by 439 publications

References 39 publications

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

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