Computational Studies on Fatty Acid Synthesis: From Mechanisms to Drug Design

by McKenzie, Matthew Edward

The first committed steps of the Fatty Acid synthesis pathway involves the de/carboxylation reactions of biotin. By understanding this step, potential novel antimicrobial agents could be discovered. The current tools of drug discovery can only help the research in finding and modifying potential hits. Finding a lead candidate from these programs are often equated to finding a needle in a haystack, which is due to the many assumptions used in molecular docking. The fundamental reaction kinetics can not be described by these techniques and a detailed study of the decarboxylation reaction is investigated using ab initio molecular dynamics. In this particular study, Car-Parrinello molecular dynamics is used and how the biotin model is protonated was found to play an important role in its reaction barrier. Although stable in low acidic solutions, a crucial nitrogen protonation is shown to have the lowest free energy barrier which could play a pivotal role in the enzymatic mechanism. The molecular docking knowledge of potential ligand inhibitors via a low level modeling technique connected to high level quantum mechanical reaction modeling provides a synergistic route in the search for inhibitors.