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Molecules 2016, 21(11), 1591; doi:10.3390/molecules21111591

Structural Analysis of Sortase A Inhibitors

Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, Bucharest 020956, Romania
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Author to whom correspondence should be addressed.
Academic Editors: Daniela Barlocco and Fiorella Meneghetti
Received: 25 October 2016 / Revised: 12 November 2016 / Accepted: 19 November 2016 / Published: 22 November 2016
(This article belongs to the Special Issue Frontiers in Antimicrobial Drug Discovery and Design)
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Abstract

Bacterial sortases are cysteine transpeptidases that regulate the covalent linkage of several surface protein virulence factors in Gram-positive bacteria. Virulence factors play significant roles in adhesion, invasion of host tissues, biofilm formation and immune evasion, mediating the bacterial pathogenesis and infectivity. Therefore, sortases are emerging as important targets for the design of new anti-infective agents. We employed a computational study, based on structure derived descriptors and molecular fingerprints, in order to develop simple classification methods which could allow predicting low active or high active SrtA inhibitors. Our results indicate that a highly active SrtA inhibitor has a molecular weight ranging between 180 and 600, contains one up to four nitrogen atoms, up to three oxygen atoms and under 18 hydrogen atoms. Also the hydrogen acceptor number and the molecular flexibility, as assessed by the number of rotatable bounds, have emerged as the most relevant descriptors for SrtA affinity. The Bemis-Murcko scaffolding revealed favoured scaffolds as containing at least two ring structures bonded directly or merged in a condensed cycle. This data represent a valuable tool for identifying new potent SrtA inhibitors, potential anti-virulence agents targeted against Gram-positive bacteria, including multiresistant strains. View Full-Text
Keywords: cysteine transpeptidases; anti-virulence drugs; Gram-positive bacteria; classification method; rotatable bonds; hydrogen bond acceptors; Bemis-Murcko scaffolding cysteine transpeptidases; anti-virulence drugs; Gram-positive bacteria; classification method; rotatable bonds; hydrogen bond acceptors; Bemis-Murcko scaffolding
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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. (CC BY 4.0).

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MDPI and ACS Style

Nitulescu, G.; Zanfirescu, A.; Olaru, O.T.; Nicorescu, I.M.; Nitulescu, G.M.; Margina, D. Structural Analysis of Sortase A Inhibitors. Molecules 2016, 21, 1591.

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