TY - JOUR
T1 - Integrative computational protocol for the discovery of inhibitors of the Helicobacter pylori nickel response regulator (NikR)
AU - Segura-Cabrera, Aldo
AU - Guo, Xianwu
AU - Rojo-Domínguez, Arturo
AU - Rodríguez-Pérez, Mario A.
N1 - Funding Information:
This project was supported by the Consejo Nacional de Ciencia y Tecnología-México (Grant Nos. 87935 and 105532) and by the Centro de Biotecnología Genómica of Instituto Politécnico Nacional-México (Secretaría de Investigación y Posgrado, Grant No. 20091288). The authors thank the Computational Systems Biology Group from Centro Nacional de Biotecnología of Consejo Superior de Investigaciones Científicas in Madrid, Spain for providing the access to the "Trueno" cluster, and programming. Aldo Segura was awarded a fellowship by the Agencia Española de Cooperacion Internacional para el Desarrollo (MAEC-AECID-2008), IIB program. Mario A. Rodríguez-Pérez and Xianwu Guo hold a scholarship from Comisión de Operación y Fomento de Actividades Académicas of Instituto Politécnico Nacional-México.
PY - 2011/12
Y1 - 2011/12
N2 - In order to identify novel inhibitors of the Helicobacter pylori nickel response regulator (HpNikR) an integrative protocol was performed for half a million compounds retrieved from the ZINC database. We firstly implement a structure-based virtual screening to build a library of potential inhibitors against the HpNikR using a docking analysis (AutoDock Vina). The library was then used to perform a hierarchical clustering of docking poses, based on protein-contact footprints calculation from the multiple conformations given by the AutoDock Vina software, and the drug-protein interaction analyses to identify and remove potential promiscuous compounds likely interacting with human proteins, hence causing drug side effects. 250 drug-like compounds were finally proposed as non-promicuous potential inhibitors for HpNikR. These compounds target the DNA-binding sites of HpNikR so that HpNikR-compound binding could be able to mimic key interactions in the DNA-protein recognition process. HpNikR inhibitors with promising potential against H. pylori could also act against other human bacterial pathogens due to the conservation of targeting motif of NikR involved in DNA-protein interaction.
AB - In order to identify novel inhibitors of the Helicobacter pylori nickel response regulator (HpNikR) an integrative protocol was performed for half a million compounds retrieved from the ZINC database. We firstly implement a structure-based virtual screening to build a library of potential inhibitors against the HpNikR using a docking analysis (AutoDock Vina). The library was then used to perform a hierarchical clustering of docking poses, based on protein-contact footprints calculation from the multiple conformations given by the AutoDock Vina software, and the drug-protein interaction analyses to identify and remove potential promiscuous compounds likely interacting with human proteins, hence causing drug side effects. 250 drug-like compounds were finally proposed as non-promicuous potential inhibitors for HpNikR. These compounds target the DNA-binding sites of HpNikR so that HpNikR-compound binding could be able to mimic key interactions in the DNA-protein recognition process. HpNikR inhibitors with promising potential against H. pylori could also act against other human bacterial pathogens due to the conservation of targeting motif of NikR involved in DNA-protein interaction.
KW - Contact activity relationship
KW - Drug discovery
KW - Drug-protein interactions
KW - Structure-based drug design
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=84855693659&partnerID=8YFLogxK
U2 - 10.1007/s00894-011-0962-2
DO - 10.1007/s00894-011-0962-2
M3 - Artículo
SN - 1610-2940
VL - 17
SP - 3075
EP - 3084
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 12
ER -