Key result
Molecular modeling and simulation of the Kv1.5 channel identified two novel compounds with strong inhibitory potency through nonpolar interactions, primarily involving the V512 residue.
Molecular modeling identifies key interaction residues (V512) and two novel compounds with high inhibitory potency against the Kv1.5 channel, a target for atrial fibrillation.
Hypothesis-generating for Kv1.5 inhibitors in atrial fibrillation; requires in vivo validation before clinical consideration.
) and play critical role in repolarization of action potential duration. It is the most rapidly activated channel and has very little or no inactivated states. In human cardiac cells, these channels are expressed more extensively in atrial myocytes than ventricle. From the evidences of its localization and functions, Kv1.5 has been declared a selective drug target for the treatment of atrial fibrillation (AF). In this present study, we have tried to identify the rapidly activating property of Kv1.5 and studied its mode of inhibition using molecular modeling, docking, and simulation techniques. Channel in open conformation is found to be stabilized quickly within the dipalmitoylphosphatidylcholine membrane, whereas most of the secondary structure elements were lost in closed state conformation. The obvious reason behind its ultra-rapid property is possibly due to the amino acid alteration in S4-S5 linker; the replacement of Lysine by Glutamine and vice versa. The popular published drugs as well as newly identified lead molecules were able to inhibit the Kv1.5 in a very similar pattern, mainly through the nonpolar interactions, and formed sable complexes. V512 is found as the main contributor for the interaction along with the other important residues such as V505, I508, A509, V512, P513, and V516. Furthermore, two screened novel compounds show surprisingly better inhibitory potency and can be considered for the future perspective of antiarrhythmic survey.
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Bhuyan et al. (2016) studied Atrial fibrillation. Kv1.5 channel inhibitors was evaluated on Kv1.5 channel inhibition and interaction pattern. Molecular modeling and simulation of the Kv1.5 channel identified two novel compounds with strong inhibitory potency through nonpolar interactions, primarily involving the V512 residue.
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