Macrocyclic effect on inhibitory activity: a modeling study on MerTK inhibitors

Abstract

Macrocyclic ring structures could have drug-like properties such as membrane permeability, metabolic stability, binding affinity, selectivity, and high-biological activities. Synthesized macrocyclic inhibitors have been studied and the effect of ring size has gained attention from drug design community. Marsault et al. showed a positive correlation between ring size and inhibitory activity against rennin. On the other hand, De Clercq et al. suggested that there would be some optimum ring size for histone deacetylase inhibitory activity. Therefore, macrocyclic effects appear elusive while intriguing. In this study, we have selected a large set of macrocyclic inhibitors (14–20-membered rings) to study macrocyclic effect on MerTK using molecular modeling techniques. We carefully positioned all the cyclic inhibitors into the binding pocket utilizing available information obtained from both experimental and theoretical means. Then, from the resultant binding poses, the ligand–receptor interactions were analyzed. Unlike previous reports, we could not observe any relevance between ring size and inhibitory activity. However, there is a correlation between the number of hydrogen bonds and inhibitory activity. Among these hydrogen-bonding interactions, active site residues Arg727, and Asn728 as well as two signature interactions at the hinge region were found to be crucial for MerTK inhibition. Furthermore, the importance of number of hydrogen bonding was further validated statistically by means of 3D-QSAR techniques such as CoMFA and CoMSIA. The involvement of Arg727 and Asn728 was checked graphically by CoMSIA hydrogen-bonding donor map. This outcome could be helpful for more potent MerTK inhibitor design. In addition, more detailed studies on ring size effect would be desirable to understand macrocyclic effects.