Three-dimensional structure-activity relationships of drugs induced cardiovascular side effects (prolongation in the QT interval)

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1 To estimate the active conformation of drugs whose active conformations are difficult to obtain from the experimental approach, we developed the two computer programs, the CAMDAS program for a conformational analysis and the molecular superposing program. The CAMDAS is an automated conformational sampling program using molecular dynamics. The molecular superposing program aims at overlaying two molecules based on the physicochemical properties of the atomic groups in a molecule. We already reported that the method combined two procedures are useful for elucidating a pharmacophore and find the active conformation among a lot of conformations of a drug. In this study, we applied the method to investigate drugs which have side effects that prolongs QT interval. We carried out the CAMDAS calculation and the molecular superposing for those drug and estimated the active conformation and the pharmacophore with respect to the prolongation effect in the QT interval.2 Potassium channel, I_<kr> participates in the prolongation effect in the QT interval. Ikr consists of HERG and MiRP1. A pore domain of I_<kr> exists in HERG. Three dimensional structure of one of the potassium channel, KcsA is clear in Xray crystal analysis. Then the three dimensional structure model of the pore domain of HERG was created with homology modeling program (FAMS) using the KcsA as the reference structure. Energy minimized calculation of the model was performed to obtain the pore model using SYBYL. We searched for the ligand binding region on the pore model using HBOP utilized the hydrophobic potential. The binding conformation of ligand was made to docking to binding the region using Unity3D program and finally the HERG-ligand complex model was created.