title: Dynamics and modulation studies of human voltage gated Kv1.5 channel.
abstract: The voltage gated Kv1.5 channels conduct the ultrarapid delayed rectifier current (IKur) 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.
authors.affiliation: a BIF Centre, Department of Biochemistry & Biophysics , University of Kalyani , Nadia, Kalyani 741235 , West Bengal , India.
authors.forename: Rajabrata
authors.initials: R
authors.lastname: Bhuyan
authors.affiliation: b Department of Biochemistry & Biophysics , University of Kalyani , Nadia, Kalyani 741235 , West Bengal , India.
authors.forename: Alpana
authors.initials: A
authors.lastname: Seal
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D015640:Ion Channel Gating; D051666:Kv1.5 Potassium Channel / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D055550:Protein Stability; D013329:Structure-Activity Relationship
chemical_list: D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers
keywords: IKur; atrial fibrillation; inhibition; ultrarapid delayed rectifier; voltage-gated potassium channel