Molecules 2014, 19(4), 4021-4045; doi:10.3390/molecules19044021
Article

Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries

1,2,*  and 1,2
Received: 21 February 2014; in revised form: 19 March 2014 / Accepted: 25 March 2014 / Published: 2 April 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Abstract: As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2 × 108 amino-oxazole derivatives. A subset of 9 × 106 of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by eSimDock. Potentially broad-spectrum antibiotic candidates were selected based on the consensus ranking by several scoring functions including non-linear statistical models implemented in eSimDock and traditional molecular mechanics force fields. The analysis of binding poses of the top-ranked compounds docked to biotin carboxylase isoforms suggests that: (1) binding of the amino-oxazole anchor is stabilized by a network of hydrogen bonds to residues 201, 202 and 204; (2) halogenated aromatic moieties attached to the amino-oxazole scaffold enhance interactions with a hydrophobic pocket formed by residues 157, 169, 171 and 203; and (3) larger substituents reach deeper into the binding pocket to form additional hydrogen bonds with the side chains of residues 209 and 233. These structural insights into drug-biotin carboxylase interactions will be tested experimentally in in vitro and in vivo systems to increase the potency of amino-oxazole inhibitors towards both Gram-negative as well as Gram-positive species.
Keywords: biotin carboxylase; acetyl-CoA carboxylase; biotin carboxylase inhibitors; amino-oxazole; combinatorial chemistry; cheminformatics; ligand docking; virtual screening; eSimDock
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Brylinski, M.; Waldrop, G.L. Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries. Molecules 2014, 19, 4021-4045.

AMA Style

Brylinski M, Waldrop GL. Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries. Molecules. 2014; 19(4):4021-4045.

Chicago/Turabian Style

Brylinski, Michal; Waldrop, Grover L. 2014. "Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries." Molecules 19, no. 4: 4021-4045.


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