Ligand Binding to the Voltage-Gated Kv1.5 Potassium Channel in the Open State—Docking and Computer Simulations of a Homology Model

Abstract

The binding of blockers to the human voltage-gated Kv1.5 potassium ion channel is investigated using a three-step procedure consisting of homology modeling, automated docking, and binding free energy calculations from molecular dynamics simulations, in combination with the linear interaction energy method. A reliable homology model of Kv1.5 is constructed using the recently published crystal structure of the Kv1.2 channel as a template. This model is expected to be significantly more accurate than earlier ones based on less similar templates. Using the three-dimensional homology model, a series of blockers with known affinities are docked into the cavity of the ion channel and their free energies of binding are calculated. The predicted binding free energies are in very good agreement with experimental data and the binding is predicted to be mainly achieved through nonpolar interactions, whereas the relatively small differences in the polar contribution determine the specificity. Apart from confirming the importance of residues V505, I508, V512, and V516 for ligand binding in the cavity, the results also show that A509 and P513 contribute significantly to the nonpolar binding interactions. Furthermore, we find that pharmacophore models based only on optimized free ligand conformations may not necessarily capture the geometric features of ligands bound to the channel cavity. The calculations herein give a detailed structural and energetic picture of blocker binding to Kv1.5 and this model should thus be useful for further ligand design efforts.

Computer Simulations of Structure–Activity Relationships for hERG Channel Blockers

“…51 Unfortunately, to date, no investigation of sertindole block using this approach has, however, been reported. Sertindole belongs to the highly potent class of hERG blockers featuring a linear topology with a central positive ionizable nitrogen situated in a linker connecting hydrophobic groups or aromatic rings on both sides.…”

Electrostatics in Proteins and Protein–Ligand Complexes

“…The reliability of the LIE model in reproducing experimentally determined binding free energies has been extensively tested in recent years [69][70][71], and results showed the average unsigned error of 0.8 kcal/mol in predicting binding free energy of binding a set of nonnucleoside inhibitors to HIV-1 reverse transcriptase [72]. The LIE model was successfully used in combination with docking algorithms and proved to be able to correctly predict binding modes for a set of HIV-1 reverse transcriptase inhibitors [70,72].…”

Interaction of local anesthetics with the K+channel pore domain

“…[28][29][30] Block of Kv1.5 by LAs and related drugs has been studied extensively by traditional electrophysiological approaches; 25,[31][32][33] however, recent work revealed a new mode of action of the anti-arrhythmic drug, quinidine. Block of Kv1.5 by quinidine with a half-inhibition constant, K 0.5 = 1 μM, in atrial myocytes induces rapid internalization (~10 min) of the channel protein.…”

“…Such a sequence alignment has previously been used to construct molecular models of the drug binding sites of Kv1.5 and hERG based on known crystal structures of K + channel proteins such as KcsA and Kv1.2. 17,19,25,[28][29][30] Mutational scanning of this region conducted to identify potential drug-binding residues of Kv1.5 found the greatest loss in drug blocking affinity for mutation of the following residues: Thr479, Thr480, Ile 502, Val505, Leu 506, Ile508 and Val512. 10,25,33 Similarly, mutation of the following residues of hERG produced the greatest loss in drug blocking affinity: Thr623, Ser624, Val625, Gly648, Tyr652 and Phe656.…”