Computational analysis of a dihydroxyflavone and a benzylideneoxyindole derivative for glaucoma-associated myocilin: insights into their molecular interactions and influence on hydration dynamics.

Glaucoma, when associated with pathogenic myocilin mutations, is caused due to myocilin misfolding and aggregation. These mutations accumulate mainly in the olfactomedin domain (mOLF) of myocilin. Two small molecules, a benzylideneoxyindole derivative (BOD) and a dihydroxyflavone (DHF), were the earliest ligands suggested to be anti-aggregation lead compounds for myocilin-associated glaucoma, following experimental observation of reduced mOLF amyloid fibrillization in vitro. The present work aims to computationally investigate these experimentally proposed lead compounds to gain insight into their binding affinities for both the wild-type (WT) and the I477N variant, and the specific interactions of the lead compounds with the mOLF domain. The influence of these small molecules on the local structure and dynamics of hydration water around the mOLF domain is also studied. On the basis of molecular docking, molecular-dynamics simulation, MM-PBSA and per-residue energy decomposition analysis, it was found that DHF exhibits subtly more favorable binding to both the mutant and the WT systems compared to BOD. Additionally, the binding of DHF to both mutant and WT systems is likely influenced more by factors other than solvation. These systems have enhanced hydration water density around them and are conformationally more stable than the BOD systems. Overall, our results offer insight that could inform future structure-based design of anti-aggregation therapies or help in rational optimization of the existing lead compounds.