TY - JOUR
T1 - Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach
AU - Pauli, Ivani
AU - Dos Santos, Ricardo N.
AU - Rostirolla, Diana C.
AU - Martinelli, Leonardo K.
AU - Ducati, Rodrigo G.
AU - Timmers, Luís F.S.M.
AU - Basso, Luiz A.
AU - Santos, Diógenes S.
AU - Guido, Rafael V.C.
AU - Andricopulo, Adriano D.
AU - Norberto De Souza, Osmar
PY - 2013/9/23
Y1 - 2013/9/23
N2 - Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted of using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC50 values ranging from 24 (±2) μM to 83 (±5) μM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with Ki values of 24 (±3) μM and 20 (±2) μM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.
AB - Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted of using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC50 values ranging from 24 (±2) μM to 83 (±5) μM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with Ki values of 24 (±3) μM and 20 (±2) μM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.
UR - http://www.scopus.com/inward/record.url?scp=84884567429&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884567429&partnerID=8YFLogxK
U2 - 10.1021/ci400202t
DO - 10.1021/ci400202t
M3 - Article
C2 - 23889525
AN - SCOPUS:84884567429
SN - 1549-9596
VL - 53
SP - 2390
EP - 2401
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 9
ER -