Computational screening of natural proteins for morita-baylis-hillman activity

Morita-Baylis-Hillman (MBH) reaction is a versatile C-C coupling reaction between an α,β- unsaturated carbonyl compound and an aldehyde, activated ketone or other carbon electrophiles in the presence of a nucleophilic catalyst. MBH adducts are densely functionalized molecules displaying wide range of biological activities. However, even in the presence of the most efficient organocatalysts, reaction rate is exceedingly slow for substrates of pharmaceutical interest. The aim of this project is to computationally explore natural proteins that contain the required catalytic machinery in the optimal three-dimensional arrangement to catalyze the MBH reaction. Two main theozyme models were used as templates to construct various catalytic atom maps (CAMs) which were later used to screen the protein databank. Promising matches (2BDB, 2NW6, 1FFE) were subjected to molecular dynamics (MD) simulations and the catalytic contacts were evaluated in a dynamic solvated environment. MD simulations showed that 2BDB could potentially show promiscuous activity for the MBH substrates that can be enhanced using active site redesign in a further study.