Uncovering false positives on a virtual screening search for cruzain inhibitors.
Some unexpected promiscuous inhibitors were observed in a virtual screening protocol applied to select cruzain inhibitors from the ZINC database. Physical-chemical and pharmacophore model filters were used to reduce the database size. The selected compounds were docked into the cruzain active site. Six hit compounds were tested as inhibitors. Although the compounds were designed to be nucleophilically attacked by the catalytic cysteine of cruzain, three of them showed typical promiscuous behavior, revealing that false positives are a prevalent concern in VS programs.
Malvezzi
Alberto
A
Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, C.P. 26077, 05513-970 São Paulo, SP, Brazil.
de Rezende
Leandro
L
Izidoro
Mario Augusto
MA
Cezari
Maria Helena Sedenho
MH
Juliano
Luiz
L
do Amaral
Antonia
A
D001665:Binding Sites; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005189:False Positive Reactions; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology
D015853:Cysteine Proteinase Inhibitors; D007659:Ketones; D009570:Nitriles; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D012664:Semicarbazones; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi