In silico identification of PAP-1 binding sites in the Kv1.2 potassium channel.
Voltage-gated potassium channels of the Kv1 family play a crucial role in the generation and transmission of electrical signals in excitable cells affecting neuronal and cardiac activities. Small-molecule blockage of these channels has been proposed to occur via a cooperative mechanism involving two main blocking sites: the inner-pore site located below the selectivity filter, and a side-pocket cavity located between the pore and the voltage sensor. Using 0.5 μs molecular dynamics simulation trajectories complemented by docking calculations, the potential binding sites of the PAP-1 (5-(4-phenoxybutoxy)psoralen) blocker to the crystal structure of Kv1.2 channel have been studied. The presence of both mentioned blocking sites at Kv1.2 is confirmed, adding evidence in favor of a cooperative channel blockage mechanism. These observations provide insight into drug modulation that will guide further developments of Kv inhibitors.
†Department of Chemistry, Britannia House, 7 Trinity Street, King's College London, London SE1 1DB, U.K.
Christian
C
Jorgensen
†Department of Chemistry, Britannia House, 7 Trinity Street, King's College London, London SE1 1DB, U.K.
Leonardo
L
Darré
‡Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, 20 Penn Street, Baltimore, Maryland 21201, United States.
Kenno
K
Vanommeslaeghe
§Worldwide Medicinal Chemistry, Pfizer Neusentis, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, U.K.
Kiyoyuki
K
Omoto
§Worldwide Medicinal Chemistry, Pfizer Neusentis, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, U.K.
David
D
Pryde
†Department of Chemistry, Britannia House, 7 Trinity Street, King's College London, London SE1 1DB, U.K.|∥Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
Carmen
C
Domene
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016000:Cluster Analysis; D003460:Crystallization; D004563:Electrochemistry; D005363:Ficusin / Q000737:chemistry*; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009474:Neurons / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D017386:Sequence Homology, Amino Acid; D012997:Solvents / Q000737:chemistry
D051663:Kv1.2 Potassium Channel; D008024:Ligands; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D012997:Solvents; D005363:Ficusin
docking; ion channels; molecular dynamics simulations; voltage gated ion channels