One of the reasons why infections become chronic, is that some bacterial cells become dormant and survive antibiotic treatment. These cells are a bacterial phenotype called persisters. One of the hypothesis for their formation is based on the so-called stringent response, a signalling cascade leading to metabolic slowdown. The first step of the stringent response cascade is the accumulation of guanosine pentaphosphate (pppGpp) or tetraphosphate (ppGpp), collectively called (p)ppGpp. The synthesis of this molecule is catalyzed by the RelA/SpoT homolog (RSH) enzyme superfamily. In order to synthetize new potential inhibitors against these enzymes to stop or to reduce the synthesis of (p)ppGpp, we performed virtual screening of several commercially available fragment libraries using a validated docking protocol within the SCHRÖDINGER® suite (Glide v. 10, Maestro). The highest scoring fragments were analysed and the four main chemotypes expanded based on structural similarity using Pubchem. Useful structural information was gathered for the design of the first generation of RSH inhibitors. The preliminary results of this work will be presented.

Structure based design of RSH inhibitors / C. Coppa, M. Civera, S. Sattin. ((Intervento presentato al 6. convegno Computationally Driven Drug Discovery Meeting CDDD tenutosi a Roma nel 2019.

Structure based design of RSH inhibitors

C. Coppa
Primo
Investigation
;
M. Civera
Secondo
Supervision
;
S. Sattin
Ultimo
Supervision
2019

Abstract

One of the reasons why infections become chronic, is that some bacterial cells become dormant and survive antibiotic treatment. These cells are a bacterial phenotype called persisters. One of the hypothesis for their formation is based on the so-called stringent response, a signalling cascade leading to metabolic slowdown. The first step of the stringent response cascade is the accumulation of guanosine pentaphosphate (pppGpp) or tetraphosphate (ppGpp), collectively called (p)ppGpp. The synthesis of this molecule is catalyzed by the RelA/SpoT homolog (RSH) enzyme superfamily. In order to synthetize new potential inhibitors against these enzymes to stop or to reduce the synthesis of (p)ppGpp, we performed virtual screening of several commercially available fragment libraries using a validated docking protocol within the SCHRÖDINGER® suite (Glide v. 10, Maestro). The highest scoring fragments were analysed and the four main chemotypes expanded based on structural similarity using Pubchem. Useful structural information was gathered for the design of the first generation of RSH inhibitors. The preliminary results of this work will be presented.
Chronic infection; Persistence; Virtual screening; Library expansion; Drug discovery
Settore CHIM/01 - Chimica Analitica
Settore CHIM/02 - Chimica Fisica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/09 - Farmaceutico Tecnologico Applicativo
Settore MED/04 - Patologia Generale
Società Chimica Italiana
Structure based design of RSH inhibitors / C. Coppa, M. Civera, S. Sattin. ((Intervento presentato al 6. convegno Computationally Driven Drug Discovery Meeting CDDD tenutosi a Roma nel 2019.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/828002
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