Computational study of paroxetine-like inhibitors reveals new molecular insight to inhibit GRK2 with selectivity over ROCK1.

The G-protein coupled receptor kinase 2 (GRK2) regulates the desensitization of beta-adrenergic receptors (ß-AR), and its overexpression has been implicated in heart failure. Hence, the inhibition of GRK2 is considered to be an important drug target for the treatment of heart failure. Due to the high sequence similarity of GRK2 with the A, G, and C family (AGC family) of kinases, the inhibition of GRK2 also leads to the inhibition of AGC kinases such as Rho-associated coiled-coil kinase 1 (ROCK1). Therefore, unraveling the mechanisms to selectively inhibit GRK2 poses an important challenge. We have performed molecular docking, three dimensional quantitative structure activity relationship (3D-QSAR), molecular dynamics (MD) simulation, and free energy calculations techniques on a series of 53 paroxetine-like compounds to understand the structural properties desirable for enhancing the inhibitory activity for GRK2 with selectivity over ROCK1. The formation of stable hydrogen bond interactions with the residues Phe202 and Lys220 of GRK2 seems to be important for selective inhibition of GRK2. Electropositive substituents at the piperidine ring and electronegative substituents near the amide linker between the benzene ring and pyrazole ring showed a higher inhibitory preference for GRK2 over ROCK1. This study may be used in designing more potent and selective GRK2 inhibitors for therapeutic intervention of heart failure.

Molecular docking and 3D QSAR studies of Chk2 inhibitors.

Isothiazole-carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three-dimensional quantitative structure-activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method-1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand-based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor-guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule-7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method-2 and 3. These methods were used for 3D QSAR. The geometrical method-3-based comparative molecular field analysis (q(2) = 0.75, r(2) = 0.87 and r(2) (predict) = 0.81) and comparative molecular similarity indices analysis (q(2) = 0.90, r(2) = 0.96 and r(2) (predict) = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor-guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.

Molecular recognition of a fluoride anion receptor: the importance of C-H (N-H)F(-) and "electropositive field space"F(-) interactions.

Host molecules effectively prefer to recognize F- ion rather than H2O through the upper rim, utilizing strong C-H (N-H)F- interactions. The electropositive field space ("electropositive field space") at the lower rim of the host molecules can also act as a good binding site for small anions such as F-. The electron withdrawing substituent at the para-position (X) makes the C(N)-HaF- and C(N)-HaO interactions much enhanced. The calculated vibrational frequencies and NMR chemical shifts are consistent with experimental trends.