Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

Abstract

Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most activecompound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes.

COX Inhibition Profiles and Molecular Docking Studies of the Lignan Hinokinin and Some Synthetic Derivatives

“…Poses with RMSD≤2.0 Å were assumed as equivalent while 2.0 Å<RMSD≤3.0 Å indicated a partial equivalence . These criteria were established by the work of Vieth et al .…”

“…As observed, all compounds displayed RMSD values within the threshold stablished for the analysis, except by the poses of compound 2 for COX‐2 (Table ) generated by the Maestro 10.1 software . Therefore, this particular docking output was discarded for the analyses.…”

Combination of network and molecule structure accurately predicts competitive inhibitory interactions

“…Moreover, not all inhibitors are structurally similar to the substrates of the regulated enzyme. While molecular docking approaches provide one means to narrow down the set of metabolites that can act as CIs [12] , [13] , [14] , they are limited to proteins with resolved crystal structure [15] . Therefore, this approach is currently unfeasible for genome-scale studies of competitive inhibitory regulatory interactions.…”

Searching for Chymase Inhibitors among Chamomile Compounds Using a Computational-Based Approach

“…Therefore, there is an interest in developing specific chymase inhibitors for their use, either alone or in combination with other agents, as new therapeutic regimens for cardiovascular diseases [4]. During the last 20 years, several known synthetic peptide and nonpeptide inhibitors of chymase have been synthesized [6,7,8,9,10], and also computational approaches have been used to find new inhibitors, by applying different procedures to design or to search for suitable molecules among different databases of chemical compounds [11,12,13]. However, the search for new inhibitors is still ongoing, and new fields can be explored to find active compounds.…”