Homology Model of Dihydropyridine Receptor: Implications for L-type Ca2+ Channel Modulation by Agonists and Antagonists

Zhorov, Boris S.; Folkman, Ekaterina V.; Ananthanarayanan, Vettai S.

doi:10.1006/abbi.2001.2484

Cited by 65 publications

(90 citation statements)

References 62 publications

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“…In 2001, Zhorov et al built two models of the pore region of Ca V 1.2 from rabbit cardiac muscle, and docked nifedipine into the active site to explore the interactions of agonists and antagonists. 40) In 2003, Lipkind and Fozzard constructed the inner pore structure of Ca V 1.2 and predicted the binding conformations of nifedipine, phenylalkylamine and agonist Bay K8644 by using the molecular Recently, the crystal structure of the voltage-gated calcium channel from bacterium Arcobacter butzleri (Ca V Ab) was reported (PDB entry: 4MS2), with a pore-motif that is structurally related to vertebrate VGCCs. The residues forming the inner low-affinity site of Ca V Ab are still present in vertebrate channels.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

El‐Moselhy

Sidhom

Esmat

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC 50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3-and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure-activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr) 4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3-and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.Key words calcium channel; dihydropyridine; docking; synthesis; three-dimensional quantitative structureactivity relationship (3D-QSAR) Precise regulation of calcium homeostasis is crucial for many physiological functions.1) Divergent types of calcium channels and pumps can control the influx of calcium ions into cells.2,3) Consequently, targeting calcium channels is advantageously beneficial to yield useful drugs. Ca V 1.2 blockers can be roughly categorized into three different chemical classes: 1,4-dihydropyridine (DHP) derivatives, phenylalkylamine derivatives and benzothiazepine derivatives. Among them, DHP derivatives have the most significant pharmacological importance. For example, amlodipine is among the top-five best selling drugs in the treatment of cardiovascular diseases. Various modulators can potentiate or block calcium entry through L-type calcium channels. [4][5][6] Calcium antagonists have a versatile pharmacological activity such as antihypertensive and antianginal, 7-9) antitumor, 10,11) anti-inflammatory, 12,13) antitubercular, 14,15) anticonvulsant and antithrombotic. 16,17) 1,4-DHPs bind selectively to L-type calcium channel protein, precisely at the transmembrane domain IIIS6 and IVS6 regions of the α1 subunit.18) The twelve approved DHP calcium antagonists developed are vasodilators.19) Vasodilatation is due to the uncoupling of the contractile mechanism of vascular smooth muscle, which requires Ca 2+ . 20)Structure-activity relationship (SAR) of DHP 21) and the clinical usage of nifedipine have promoted us to synthesize two series of nifedipine analogues where the ortho-or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking st...

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Section: Resultsmentioning

confidence: 99%

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

El‐Moselhy

Sidhom

Esmat

et al. 2017

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The coordination pattern of Ca 2ϩ ions in the EEEE ring is unknown. Asymmetric split (24) and symmetric single-file (35) models were considered. Recent calculations predict that both models are energetically possible (36).…”

Section: Resultsmentioning

confidence: 99%

“…Published models suggest different locations of dihydropyridines in the channel (24,55,56). Further studies are necessary to elaborate a model of simultaneous binding of dihydropyridine and BTZ ligands in the L-type Ca 2ϩ channel.…”

Section: Channelmentioning

confidence: 99%

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Tikhonov

Zhorov

2008

Journal of Biological Chemistry

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In our open channel model, key functional groups of BTZs interact with BTZ-sensing residues, which were identified in previous mutational experiments. The bulky tricyclic moiety occupies interface between domains III and IV, while the ammonium group protrudes into the inner pore, where it is stabilized by nucleophilic C-ends of the pore helices. In the closed channel model, contacts with several ligand-sensing residues in the inner helices are lost, which weakens ligand-channel interactions. An important feature of the ligand-binding mode in both open and closed channels is an interaction between the BTZ carbonyl group and a Ca 2؉ ion chelated by the selectivity filter glutamates in domains III and IV. In the absence of Ca 2؉ , the tricyclic BTZ moiety remains in the domain interface, while the ammonium group directly interacts with a glutamate residue in the selectivity filter. Our model suggests that the Ca 2؉ potentiation involves a direct electrostatic interaction between a Ca 2؉ ion and the ligand rather than an allosteric mechanism. Energy profiles indicate that BTZs can reach the binding site from the domain interface, whereas access through the open activation gate is unlikely, because reorientation of the bulky molecule in the pore is hindered. Benz(othi)azepines (BTZs)2 represent one of three main classes of ligands of L-type calcium channels (1, 2). Tonic (resting) block of Ca 2ϩ channels is usually measured by applying infrequent depolarization stimuli. Frequency-dependent block is measured during more rapid trains of depolarization stimuli. Increasing the stimulation frequency generally leads to more effective inhibition by BTZs (3-5). Voltage and activation dependence of the block are consistent with the idea that different functional states of the channel have different affinities for the drug in the order inactivated Ͼ open Ͼ closed state. These observations are consistent with the "modulated receptor" hypothesis (6), which was initially proposed to explain the action of local anesthetics on Na ϩ channels. The effect of BTZs also depends on the ionic environment. Raising concentrations of Ca 2ϩ or Ba 2ϩ antagonize diltiazem block (3). However, the block is more pronounced when Ca 2ϩ rather than Ba 2ϩ is used as a charge carrier (3, 7), and thus the block is considered potentiated by Ca 2ϩ (7). The conductance with Ba 2ϩ is higher than with Ca 2ϩ , because Ca 2ϩ binds more tightly to the outer-pore glutamates (8). These experiments suggest that the high affinity binding of BTZs requires a cation binding in the channel.Extracellular applications of both the tertiary and quaternary BTZ analogs effectively block Ca 2ϩ channels. In contrast, intracellular application of the same compounds does not result in significant block, leading to the conclusion that BTZs block the channels via an extracellular pathway (9 -11).Mutational studies have largely delimited BTZ-sensing residues to the inner helices and P-loops of domains III and IV (see Table 1). However, applying experimental data for mapping the BTZ...

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“…Homology models of NaV1.4 and CaV1.2 channels were built from the P-loop and S6 segments using the sequence alignments with potassium channels proposed before (7). The backbones of the ascending limbs were initially folded as in Ref.…”

Section: Methodsmentioning

confidence: 99%

Possible Roles of Exceptionally Conserved Residues around the Selectivity Filters of Sodium and Calcium Channels

Tikhonov

Zhorov

2011

Journal of Biological Chemistry

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In the absence of x-ray structures of sodium and calcium channels their homology models are used to rationalize experimental data and design new experiments. A challenge is to model the outer-pore region that folds differently from potassium channels. Here we report a new model of the outer-pore region of the NaV1.4 channel, which suggests roles of highly conserved residues around the selectivity filter. The model takes from our previous study (Tikhonov, D. B., and Zhorov, B. S. (2005) Biophys. J. 88, 184 -197) the general disposition of the P-helices, selectivity filter residues, and the outer carboxylates, but proposes new intra-and inter-domain contacts that support structural stability of the outer pore. Glycine residues downstream from the selectivity filter are proposed to participate in knob-into-hole contacts with the P-helices and S6s. These contacts explain the adapted tetrodotoxin resistance of snakes that feed on toxic prey through valine substitution of isoleucine in the P-helix of repeat IV. Polar residues five positions upstream from the selectivity filter residues form H-bonds with the ascending-limb backbones. Exceptionally conserved tryptophans are engaged in inter-repeat H-bonds to form a ring whose -electrons would facilitate passage of ions from the outer carboxylates to the selectivity filter. The outerpore model of CaV1.2 derived from the NaV1.4 model is also stabilized by the ring of exceptionally conservative tryptophans and H-bonds between the P-helices and ascending limbs. In this model, the exceptionally conserved aspartate downstream from the selectivity-filter glutamate in repeat II facilitates passage of calcium ions to the selectivity-filter ring through the tryptophan ring. Available experimental data are discussed in view of the models.Voltage-gated ion channels are involved in the control of many physiological functions. Upon membrane depolarization, channels rapidly transit from the resting to the open state, then close to inactivated state(s), and return to the resting state upon membrane repolarization. The human genome encodes nine voltage-gated sodium (NaV1.1-NaV1.9) and ten voltage-gated calcium channels categorized as L (CaV1.1-CaV1.4), P/Q (CaV2.1), N (CaV2.2), R (CaV2.3), and T (CaV3.1-CaV3.3) types. The pore-forming ␣ 1 -subunit of calcium and sodium channels folds from a single polypeptide chain of four homologous repeats (Fig. 1A). Repeats I to IV are arranged clockwise when viewed extracellularly (1). Each repeat contains a voltage-sensing domain S1-S4, an outer helix S5, an inner helix S6, and a membrane-diving P-loop between S5 and S6. The P-loop includes a P-helix, a P-turn, and an ascending limb. Four ascending limbs, which line the outer pore, contain selectivity-filter residues in positions p50 (see Footnote 2 for residue labels). 2 Repeats I, II, III, and IV contain selectivity-filter glutamates in calcium channels (the EEEE ring) and Asp, Glu, Lys, and Ala residues in sodium channels (the DEKA ring). The ascending limbs also contain the outer carboxylates t...

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Homology Model of Dihydropyridine Receptor: Implications for L-type Ca2+ Channel Modulation by Agonists and Antagonists

Cited by 65 publications

References 62 publications

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

Synthesis, Docking Simulation, Biological Evaluations and 3D-QSAR Study of 1,4-Dihydropyridines as Calcium Channel Blockers

Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel

Possible Roles of Exceptionally Conserved Residues around the Selectivity Filters of Sodium and Calcium Channels

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