Structure-based virtual screening and electrophysiological evaluation of new chemotypes of K(v)1.5 channel blockers.
Atrial fibrillation (AF) is the most prevalent nonfatal cardiac rhythm disorder associated with an increased risk of heart failure and stroke. Considering the ventricular side effects induced by anti-arrhythmic agents in current use, K(v)1.5 channel blockers have attracted a great deal of deliberation owing to their selective actions on atrial electrophysiology. Herein we report new chemotypes of K(v)1.5 channel blockers that were identified through a combination of structure-based virtual screening and in silico druglike property prediction including six scoring functions, as well as electrophysiological evaluation. Among them, five of the 18 compounds exhibited >50 % blockade ratio at 10 microM, and have structural features different from conventional K(v)1.5 channel blockers. These novel scaffolds could serve as hits for further optimization and SAR studies for the discovery of selective agents to treat AF.
Yang
Qian
Q
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, Jiangsu, China.
Fedida
David
D
Xu
Hongjian
H
Wang
Binghe
B
Du
Lupei
L
Wang
Xiaojian
X
Li
Minyong
M
You
Qidong
Q
D001665:Binding Sites; D003198:Computer Simulation; D055724:Electrophysiological Phenomena; D057166:High-Throughput Screening Assays; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers