Title: Putative inhibitors of homology-modelled chorismate synthase of Shigella flexneri

Authors: Catherine Jessica Yihui Lai

Addresses: Department of Psychology, Stanford University, Stanford, CA 94309, USA

Abstract: Shigellosis is an infection of the intestinal epithelium. We focus on the multidrug-resistant S. flexneri (MDRSf) pathogen. We chose as our target chorismate synthase (SfCS), a key enzyme in the biosynthesis of aromatic amino acids in the shikimate-chorismate pathway. The SfCS crystal structure is unknown, so we built a homology model using the SfCS Serotype 2a sequence. Using the model, clusters of protein-protein interaction anchor residue hotspots were obtained, upon which a pharmacophore model was built. Virtual screening on 22,723,923 compounds resulted in seven hits. Of these, one was admissible against checks for ADME-Tox pharmacokinetics and cytochrome P450 toxicities. A scaffold-hopping procedure resulted in two other candidates. All three were docked to pockets determined using a new measure of residue depth associated with the Voronoi procedure. Remarkably, the three putative inhibitors have high pIC50 values that exceed those of many common antibiotics now in use.

Keywords: shigellosis; diseases of the poor; pharmacophore; virtual screening; scaffold-hopping.

DOI: 10.1504/IJCBDD.2018.094631

International Journal of Computational Biology and Drug Design, 2018 Vol.11 No.3, pp.255 - 273

Received: 26 Jun 2017
Accepted: 21 Nov 2017
Published online: 10 Sep 2018 *

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