Molecular docking study of the binding of aminopyridines within the K+ channel

Abstract

We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K(+) channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the alpha-subunit of the K(+) channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K(+) channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3-7 kcal mol(-1). On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.

Inhibitory activities and possible anticancer targets of Ru(II)-based complexes using computational docking method

“…However, the order of ranked best complexes may not be completely absolute since the reliability of the order for autodock is ∼2.177 kcal/mol standard error [31,32] and the difference between the best ranked is not up to 2.1 kcal/mol (Table 2) as our chosen interval which is a little stringent than reported ∼2.177 kcal/mol. Those that are still within the range of 2.1 kcal/mol as the predicted best inhibitor of HDAC7 are 8 followed by 1, 2, 3 and 4 respectively.…”

“…In Autodock, the Lamarckian genetic algorithm is chosen because it has been pointed out to be most efficient, reliable and successful than others such as simulated annealing (SA) and a generic genetic algorithm (GA) methods in autodock [31,32]. For the Ru atom charge, we applied the native charge of +2 which is general and can be applied to any complex/receptor interaction study though it may not be as accurate as using an optimized charge which is more specific to the type of the system as it was reported for the docking of the metalloenzymes that contain Zn atom [26].…”

“…The correlation of ranking order of the complexes from Autodock and Glide in Table 4 further gave a clear picture of the disparity in their ranking as most of the correlation determined for each receptor are highly negative which is an indication that the ranking of the complex activities by the two method are nearly reverse of each other. However, the comparison between the activities of the complexes predicted by the two methods of docking are not of interest, but the interest is to understand and to predict the optimal orientation and conformation of the complexes embedded in a proteins which is the primary objective of all the research efforts in the area of protein-ligand interactions, development of many different techniques and the associated software tools [32]. Also, being careful of the inherent inaccuracies in the calculated estimates of the binding energy by each of the different docking method, the binding energy cannot be directly compared and used for hit-ranking since the values are calculated using different docking programs with different force-fields [39].…”

Comparative Normal/Failing Rat Myocardium Cell Membrane Chromatographic Analysis System for Screening Specific Components That Counteract Doxorubicin-Induced Heart Failure from Acontium carmichaeli

“…In particular, Thr107 was also one of the binding sites of the selective K + channel blocker 4-AP. 58 Recent reports have suggested that the binding pocket and the pore region of K + channel consist of key residues (Thr, Ile, Gly, Phe, and Ala), which form the selectivity filter of the K + channel. 59 Our docking results suggest that 14-acetyl-TALA and TALA block the Kv channel by entering the selectivity filter to suppress the K + efflux, thus protecting myocardial cells from apoptosis.…”

Elucidating the Molecular Basis of Action of a Classic Drug: Guanidine Compounds As Inhibitors of Voltage-Gated Potassium Channels

“…This information has been judiciously used for rational drug design on the aminopyridine template. For example, docking simulations on the binding site (Caballero et al, 2007) have facilitated structure-activity studies on aminopyridines, leading to the generation of molecules with better therapeutic indices (Mayorov et al, 2010). In contrast, the mechanism of inhibition of Kv channels by guanidine has never been investigated thoroughly, and there are no published structure-activity studies on the guanidine scaffold.…”