TY - JOUR
T1 - Conf-VLKA: A structure-based revisitation of the Virtual Lock-and-key Approach
AU - Almerico, Anna Maria
AU - Tutone, Marco
AU - Perricone, Ugo
PY - 2017
Y1 - 2017
N2 - In a previous work, we developed the in house Virtual Lock-and-Key Approach (VLKA) in order to evaluate target assignment starting from molecular descriptors calculated on known inhibitors used as an information source. This protocol was able to predict the correct biological target for the whole dataset with a good degree of reliability (80%), and proved experimentally, which was useful for the target fishing of unknown compounds. In this paper, we tried to remodel the previous in house developed VLKA in a more sophisticated one in order to evaluate the influence of 3D conformation of ligands on the accuracy of the prediction. We applied the same previous algorithm of scoring and ranking but, this time, combining it with a structure-based approach as docking. For this reason, we retrieved from the RCSB Protein Data Bank (PDB), the available 3D structures of the biological targets included into the previous work, and we used them to calculate poses of the 7352 dataset compounds in the VLKA biological targets. First, docking protocol has been used to retrieve docking scores, then, from the docked poses of each molecule, 3D-descriptors were calculated (Conf-VLKA), While the use of the simple docking scores proved to be inadequate to improve compounds classification, the Conf-VLKA showed some interesting variations compared to the original VLKA, especially for targets whose ligands present a high number of rotamers. This work represent a first preliminary study to be completed using other techniques such as induced fit docking or molecular dynamics structure clustering to take into account the protein side chains adaptation to ligands structures.
AB - In a previous work, we developed the in house Virtual Lock-and-Key Approach (VLKA) in order to evaluate target assignment starting from molecular descriptors calculated on known inhibitors used as an information source. This protocol was able to predict the correct biological target for the whole dataset with a good degree of reliability (80%), and proved experimentally, which was useful for the target fishing of unknown compounds. In this paper, we tried to remodel the previous in house developed VLKA in a more sophisticated one in order to evaluate the influence of 3D conformation of ligands on the accuracy of the prediction. We applied the same previous algorithm of scoring and ranking but, this time, combining it with a structure-based approach as docking. For this reason, we retrieved from the RCSB Protein Data Bank (PDB), the available 3D structures of the biological targets included into the previous work, and we used them to calculate poses of the 7352 dataset compounds in the VLKA biological targets. First, docking protocol has been used to retrieve docking scores, then, from the docked poses of each molecule, 3D-descriptors were calculated (Conf-VLKA), While the use of the simple docking scores proved to be inadequate to improve compounds classification, the Conf-VLKA showed some interesting variations compared to the original VLKA, especially for targets whose ligands present a high number of rotamers. This work represent a first preliminary study to be completed using other techniques such as induced fit docking or molecular dynamics structure clustering to take into account the protein side chains adaptation to ligands structures.
KW - Biological target
KW - Computer Graphics and Computer-Aided Design
KW - Descriptors
KW - Docking
KW - Inhibitors
KW - Ligand-based
KW - Materials Chemistry2506 Metals and Alloys
KW - Physical and Theoretical Chemistry
KW - Spectroscopy
KW - Structure-based
KW - Target fishing
KW - Vlka
KW - Biological target
KW - Computer Graphics and Computer-Aided Design
KW - Descriptors
KW - Docking
KW - Inhibitors
KW - Ligand-based
KW - Materials Chemistry2506 Metals and Alloys
KW - Physical and Theoretical Chemistry
KW - Spectroscopy
KW - Structure-based
KW - Target fishing
KW - Vlka
UR - http://hdl.handle.net/10447/211975
UR - http://www.elsevier.com/inca/publications/store/5/2/5/0/1/2/index.htt
M3 - Article
VL - 71
SP - 50
EP - 57
JO - JOURNAL OF MOLECULAR GRAPHICS & MODELLING
JF - JOURNAL OF MOLECULAR GRAPHICS & MODELLING
SN - 1093-3263
ER -