Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach

Ivani Pauli, Ricardo N. Dos Santos, Diana C. Rostirolla, Leonardo K. Martinelli, Rodrigo G. Ducati, Luís F S M Timmers, Luiz A. Basso, Diógenes S. Santos, Rafael V C Guido, Adriano D. Andricopulo, Osmar Norberto De Souza

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2390-2401
Number of pages12
JournalJournal of Chemical Information and Modeling
Volume53
Issue number9
DOIs
StatePublished - Sep 23 2013
Externally publishedYes

Fingerprint

contagious disease
Screening
Enzymes
Ligands
Molecules
drug
Substrates
NAD
Crystal structure
Values
candidacy
Pharmaceutical Preparations
interaction

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Pauli, I., Dos Santos, R. N., Rostirolla, D. C., Martinelli, L. K., Ducati, R. G., Timmers, L. F. S. M., ... Norberto De Souza, O. (2013). Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach. Journal of Chemical Information and Modeling, 53(9), 2390-2401. https://doi.org/10.1021/ci400202t

Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach. / Pauli, Ivani; Dos Santos, Ricardo N.; Rostirolla, Diana C.; Martinelli, Leonardo K.; Ducati, Rodrigo G.; Timmers, Luís F S M; Basso, Luiz A.; Santos, Diógenes S.; Guido, Rafael V C; Andricopulo, Adriano D.; Norberto De Souza, Osmar.

In: Journal of Chemical Information and Modeling, Vol. 53, No. 9, 23.09.2013, p. 2390-2401.

Research output: Contribution to journalArticle

Pauli, I, Dos Santos, RN, Rostirolla, DC, Martinelli, LK, Ducati, RG, Timmers, LFSM, Basso, LA, Santos, DS, Guido, RVC, Andricopulo, AD & Norberto De Souza, O 2013, 'Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach', Journal of Chemical Information and Modeling, vol. 53, no. 9, pp. 2390-2401. https://doi.org/10.1021/ci400202t
Pauli, Ivani ; Dos Santos, Ricardo N. ; Rostirolla, Diana C. ; Martinelli, Leonardo K. ; Ducati, Rodrigo G. ; Timmers, Luís F S M ; Basso, Luiz A. ; Santos, Diógenes S. ; Guido, Rafael V C ; Andricopulo, Adriano D. ; Norberto De Souza, Osmar. / Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach. In: Journal of Chemical Information and Modeling. 2013 ; Vol. 53, No. 9. pp. 2390-2401.
@article{9875946db67544689087fad3641ff4e8,
title = "Discovery of new inhibitors of mycobacterium tuberculosis InhA enzyme using virtual screening and a 3D-pharmacophore-based approach",
abstract = "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.",
author = "Ivani Pauli and {Dos Santos}, {Ricardo N.} and Rostirolla, {Diana C.} and Martinelli, {Leonardo K.} and Ducati, {Rodrigo G.} and Timmers, {Lu{\'i}s F S M} and Basso, {Luiz A.} and Santos, {Di{\'o}genes S.} and Guido, {Rafael V C} and Andricopulo, {Adriano D.} and {Norberto De Souza}, Osmar",
year = "2013",
month = "9",
day = "23",
doi = "10.1021/ci400202t",
language = "English (US)",
volume = "53",
pages = "2390--2401",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "9",

}

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

VL - 53

SP - 2390

EP - 2401

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 9

ER -