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As a control, kanamycin (1C32 g mLC1) was added to samples of and with dilutions from 1 to 64 g mLC1

Posted on October 29, 2021 by president2010

As a control, kanamycin (1C32 g mLC1) was added to samples of and with dilutions from 1 to 64 g mLC1. the targets of current antibiotics but, instead, act in the same pathways as existing drugs since this might enable the restoration of drug sensitivity via combination therapy. Undecaprenyl diphosphate synthase (UPPS) is one such target. The undecaprenyl diphosphate product (UPP) is essential for bacterial cell growth because of its role in the formation of bacterial cell wall peptidoglycan,1,3 Scheme 1, and it is not produced by humans.2,4 Open in a separate window Scheme 1 Undecaprenyl Diphosphate Synthase Reaction and Relationship of UPP to Bacterial Cell Wall Biosynthesis SmithKline Beecham screened their compound collection against UPPS but reported Flt4 no chemically tractable low micromolar hits.5 Novartis pursued tetramic and tetronic acids and dihydropyridin-2-ones, but noted issues associated with human serum albumin binding and a lack of in vivo activity.6,7 Previously, we reported several potent UPPS inhibitors together with X-ray crystallographic (or modeled) binding modes for a variety of chemical classes including lipophilic bisphosphonates,8 phthalic acids,9 diketo acids,10 anthranilic acids, benzoic acids,11,12 aryl phosphonates, bis-amines, and bis-amidines.12 The most promising of these compounds, a bis-amidine, was shown to have potent activity in biochemical assays, in cellular assays, and in a murine model of MRSA infection.12 Since UPPS must bind multiple substrates (IPP, FPP, or more elongated prenyl-PP intermediates) and many inhibitors are to some degree substrate mimics, it is common to observe numerous inhibitors simultaneously bound to UPPS, with up to 4 binding sites being occupied.8 However, it is unclear whether inhibitory activity is due to binding to one specific site or to multiple sites. It has been shown that some inhibitors occupy only site 4, an allosteric site distant from the catalytic center, while others bind to site 1, the substrate binding site,12 complicating docking studies and, regardless of the inhibitor-binding mode, the flexibility of UPPS creates challenges for virtual screening. Here, to help reduce these problems we employed the 12 crystallographic structures described in previous work8,12 to select those that provided maximal enrichment in virtual screening studies. We then made predictions using these structures, leading to novel UPPS inhibitors, some with promising antibacterial activity. Methods and Materials Computational Aspects Following the methods described in previous work,12 we docked 112 known UPPS inhibitors having IC50 values <100 M, together with 1000 decoys from the Schr?dinger decoy collection (having an average molecular weight of 400 Da), to UPPS (hereafter, EcUPPS). Docking was performed using the Glide13?15 program, and compounds were ranked by their Glide XP score. The proteins were prepared by stripping water and ligand molecules, capping, and neutralizing AZ304 any unsolved loops, followed by preparation with the Schr?dinger protein preparation wizard using AZ304 standard parameters.16 After docking, compounds were ranked by their docking score, and then area under the curve (AUC) analyses were performed. Retrospective enrichment was quite good for 2/12 structures (PDB codes 2E98 and 4H3A), so we docked into these structures for the prospective studies AZ304 (Figure ?(Figure1).1). 2E98 is an EcUPPS X-ray structure containing four lipophilic AZ304 bisphosphonates (BPH-629; IC50 300 nM), which bind to sites 1C4, one inhibitor to each site.84H3A is an EcUPPS structure containing a diketo acid inhibitor AZ304 (BPH-1330) which has a 2 M IC50, and the inhibitor binds (in the solid state) only to site 4.10,12 These structures thus have significant differences: only site 4 is occupied in 4H3A, while in 2E98, all four sites are occupied and the protein is in a wide-open conformation (Figure ?(Figure22)..

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