Ionic Channels as Targets for Drug Design: A Review on Computational Methods

Fernández‐Ballester, Gregorio; Fernández-Carvajal, Asia; González-Ros, José M.; Ferrer‐Montiel, Antonio

doi:10.3390/pharmaceutics3040932

Cited by 25 publications

(17 citation statements)

References 134 publications

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“…Recently, virtual screening methods have emerged as an efficient approach for identifying potent and specific inhibitors for different ion channels (Langer and Krovat, ; Fernández‐Ballester et al ., ; Simonin et al ., ). In this study, we carried out an initial virtual screening using an in‐house developed pharmacophore similarity search algorithm: xLOS, which compared the spatial overlap between a catalogue of commercially available drug‐like small molecules to the three reference TRPM4 inhibitors, 9‐phenanthrol, glibenclamide and FFA.…”

Section: Discussionmentioning

confidence: 98%

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Ozhathil

Delalande

Bianchi

et al. 2018

British J Pharmacology

105

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Background and PurposeTRPM4 is a calcium‐activated non‐selective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small‐molecule inhibitors by combining in silico methods and cell‐based screening assay, with sub‐micromolar potency and improved selectivity from previously reported TRPM4 inhibitors.Experimental ApproachHere, we developed a high throughput screening compatible assay to record TRPM4‐mediated Na+ influx in cells using a Na+‐sensitive dye and used this assay to screen a small set of compounds selected by ligand‐based virtual screening using previously known weakly active and non‐selective TRPM4 inhibitors as seed molecules. Conventional electrophysiological methods were used to validate the potency and selectivity of the hit compounds in HEK293 cells overexpressing TRPM4 and in endogenously expressing prostate cancer cell line LNCaP. Chemical chaperone property of compound 5 was studied using Western blots and electrophysiology experiments.Key ResultsA series of halogenated anthranilic amides were identified with TRPM4 inhibitory properties with sub‐micromolar potency and adequate selectivity. We also showed for the first time that a naturally occurring variant of TRPM4, which displays loss‐of‐expression and function, is rescued by the most promising compound 5 identified in this study.Conclusions and ImplicationsThe discovery of compound 5, a potent and selective inhibitor of TRPM4 with an additional chemical chaperone feature, revealed new opportunities for studying the role of TRPM4 in human diseases and developing clinical drug candidates.

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Section: Discussionmentioning

confidence: 98%

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Ozhathil

Delalande

Bianchi

et al. 2018

British J Pharmacology

105

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“…Modeling was carried out as previously described (22,29,30). Visualization and editing of the molecules were done with Yasara (31) (http:// www.yasara.org).…”

Section: Molecular Modelingmentioning

confidence: 99%

The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating

Gregorio-Teruel

Valente

Liu

et al. 2015

Biophysical Journal

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Transient receptor potential vanilloid subtype I (TRPV1) is a thermosensory ion channel that is also gated by chemical substances such as vanilloids. Adjacent to the channel gate, this polymodal thermoTRP channel displays a TRP domain, referred to as AD1, that plays a role in subunit association and channel gating. Previous studies have shown that swapping the AD1 in TRPV1 with the cognate from the TRPV2 channel (AD2) reduces protein expression and produces a nonfunctional chimeric channel (TRPV1-AD2). Here, we used a stepwise, sequential, cumulative site-directed mutagenesis approach, based on rebuilding the AD1 domain in the TRPV1-AD2 chimera, to unveil the minimum number of amino acids needed to restore protein expression and polymodal channel activity. Unexpectedly, we found that virtually full restitution of the AD1 sequence is required to reinstate channel expression and responses to capsaicin, temperature, and voltage. This strategy identified E692, R701, and T704 in the TRP domain as important for TRPV1 activity. Even conservative mutagenesis at these sites (E692D/R701K/T704S) impaired channel expression and abolished TRPV1 activity. However, the sole mutation of these positions in the TRPV1-AD2 chimera (D692E/K701R/S704T) was not sufficient to rescue channel gating, implying that other residues in the TRP domain are necessary to endow activity to TRPV1-AD2. A biophysical analysis of a functional chimera suggested that mutations in the TRP domain raised the energetics of channel gating by altering the coupling of stimuli sensing and pore opening. These findings indicate that inter- and/or intrasubunit interactions in the TRP domain are essential for correct TRPV1 gating.

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“…2 Potassium channel druggability mechanisms remains an active area of research, for which no single unified mechanism is known. 3 Potassium channels form selective pores that span cell membranes, enabling the selective and rapid conduction of potassium ions down the electrochemical gradient. 4 Their structure comprises two or four subunits, forming dimers of dimers or tetramers.…”

Section: Introductionmentioning

confidence: 99%

“…A pore-loop structure lines the top of the pore, known as the selectivity filter that modulates the selective ion permeability. Currently, at least 60 unique potassium channel X-ray crystal structures are available, 3 of which representatives of three families of potassium channels were considered here.…”

Section: Introductionmentioning

confidence: 99%

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

et al. 2016

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Potassium channels are of paramount physiological and pathological importance and therefore constitute significant drug targets. One of the keys to rationalize the way drugs modulate ion channels is to understand the ability of such small molecules to access their respective binding sites, from which they can exert an activating or inhibitory effect. Many computational studies have probed the energetics of ion permeation, and the mechanisms of voltage gating, but little is known about the role of fenestrations as possible mediators of drug entry in potassium channels. To explore the existence, structure, and conformational dynamics of transmembrane fenestrations accessible by drugs in potassium channels, molecular dynamics simulation trajectories were analyzed from three potassium channels: the open state voltage-gated channel Kv1.2, the G protein-gated inward rectifying channel GIRK2 (Kir3.2), and the human two-pore domain TWIK-1 (K2P1.1). The main results of this work were the identification of the sequence identity of four main lateral fenestrations of similar length and with bottleneck radius in the range of 0.9-2.4 Å for this set of potassium channels. It was found that the fenestrations in Kv1.2 and Kir3.2 remain closed to the passage of molecules larger than water. In contrast, in the TWIK-1 channel, both open and closed fenestrations are sampled throughout the simulation, with bottleneck radius shown to correlate with the random entry of lipid membrane molecules into the aperture of the fenestrations. Druggability scoring function analysis of the fenestration regions suggests that Kv and Kir channels studied are not druggable in practice due to steric constraining of the fenestration bottleneck. A high (>50%) fenestration sequence identity was found in each potassium channel subfamily studied, Kv1, Kir3, and K2P1. Finally, the reported fenestration sequence of TWIK-1 compared favorably with another channel, K2P channel TREK-2, reported to possess open fenestrations, suggesting that K2P channels could be druggable via fenestrations, for which we reported atomistic detail of the fenestration region, including the flexible residues M260 and L264 that interact with POPC membrane in a concerted fashion with the aperture and closure of the fenestrations.

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Ionic Channels as Targets for Drug Design: A Review on Computational Methods

Cited by 25 publications

References 134 publications

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating

Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations

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Ionic Channels as Targets for Drug Design: A Review on Computational Methods

Cited by 25 publications

References 134 publications

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4

The Integrity of the TRP Domain Is Pivotal for Correct TRPV1 Channel Gating

Lateral Fenestrations in K+-Channels Explored Using Molecular Dynamics Simulations

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Lateral Fenestrations in K⁺-Channels Explored Using Molecular Dynamics Simulations