Abstract
Clostridium botulinum has become well known for its ability to produce the most potent toxins. These are botulinum neurotoxins (BoNTs) and are of high interest as they are classified as Category A threats by the Center of Disease Control and Prevention due to the ease of culturing and distributing this species of bacteria. They are the cause of the deadly disease, botulism. Though of imminent concern, there is still no current method of treating botulism once symptoms have begun. Thus, investigations for several small natural molecules as inhibitors of BoNTs is of utmost priority. Through induced fit docking calculations in silico, small molecule inhibitor binding mechanisms have been estimated and modifications to improve these structures have been proposed. These results support the results of a previously performed in vitro assay of these small molecules, showing promising potential as inhibitors of Botulism Neurotoxin Serotype A. The compounds of interest have all been found to be competitive inhibitors at the BoNT/A active site and the in silico results generally agree with the in vitro assay. The two main outliers of this trend are IAS008A11 and IAS006A04 and this is speculated to be due to overwhelming presence of hydrogen bond donor and acceptor groups on one side of IAS008A11 and entirely on IAS006A04 as these interactions are rewarded heavily in the XP GlideScore and by extension in Induced Fit calculations. The implications of the top performing structures and potential modifications will also be discussed.