Verapamil binding site

Figure 16.4 General pharmacophoric pattern of drugs at the verapamil-binding site of P-gp.

Reynolds, I.J., Gould, R.J., Snyder, S.H. pH] Verapamil binding sites in brain and skeletal muscle regulation by calcium, Eur. J. Pharmacol. 1983, 95, 319-321. 

Langguth, Int. J. Clin. Pharmacol. Ther., 38,168 (2000). Affinities at the Verapamil Binding Site of MDRl-Encoded P-Glycoprotein Drugs and Analogues, Stereoisomers and Metabolites. 

HSA and BSA were used as chiral selectors to separate ofloxazin, propranolol, and verapamil enantiomers. With ketoprofen and warfarin as displacers, preferred binding sites at both proteins were discussed. 

However, there have been some contradictory results. It has been reported that some modifiers do not compete with the cytotoxic agent for binding to P-gp even though they act as substrates for it [77]. In some resistant cell tines there was no correlation between an increase in MDR and the P-gp levels [79-81], The calcium channel blocker SR3357 (2) - which is 4—5 times more potent than verapamil - was shown not to compete for the binding site of the labeled [3H]-azidopine on P-gp whereas verapamil did. SR3357 did not bind to P-gp, but to a 65-kDa protein. Inter-... 

Several papers proposing multiple recognition sites for Pgp have been presented in the past. In this work, the pharmacophoric analysis of the dataset shows that the requirements to interact with Pgp are the same for all 129 compounds. Since in our database we have not included known R-site binders and anthracydines, we cannot say definitively that the pharmacophore found represents one of the binding sites that have been described in the literature. Two of the molecules present in the database, verapamil and dipyridamole, are known to bind in the H-site described by Shapiro and Ling [10]. We also cannot definitely state that the pharmacophore defines any functional site within the transporter. Further work, to try to define the location of the corresponding amino acids in a protein homology model, is in progress. 

The specific Ca channel antagoni.sts verapamil, nifedipine, and diltiazem interact at specific sites on the calcium channel protein. These blockers do not occlude the channel physically but bind to sites in the channel, as they can promote both channel activation and antagonism. AITiniiy fix binding sites on the channel varies, depending un the status of the channel. The channel can exist in either an open (0. re.sting (R). or inactivated (I) state, and the equilibrium lx-, tween them is determined by stimulus frequency and mem-... 

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