New leads of metallo-beta-lactamase inhibitors from structure-based pharmacophore design.

We have applied pharmacophore generation, database searching, docking methodologies, and experimental enzyme kinetics to discover new structures for design of di-zinc metallo-beta-lactamase inhibitors. Based on crystal structures of class B1 metallo-beta-lactamases with a succinic acid and a mercapto-carboxylic acid inhibitor bound to the enzyme, two pharmacophore models were constructed. With the Catalyst program, these pharmacophores were used to search the ACD database, which provided a total of 74 hits representing four different chemical classes of compounds: Dicarboxylic acids, phosphonic and sulfonic acid derivatives, and mercapto-carboxylic acids. All hits were docked into different metallo-beta-lactamases (from classes B1 and B3) using the GOLD docking program. A selection scheme based on the GOLD scores, the Catalyst fit and shape values, and the size of the compounds (molecular weight, surface area, and number of rotatable bonds) was developed and thirteen compounds representing all four chemical classes were selected for experimental studies. Three compounds with new scaffolds hitherto not present in metallo-beta-lactamase inhibitors have IC50 values less than 15 microM and may serve as starting points in the design of metallo-beta-lactamase inhibitors.