CoMFA and CoMSIA studies on 5-hydroxyindole-3-carboxylate derivatives as 5-lipoxygenase inhibitors: Generation of homology model and docking studies

https://doi.org/10.1016/j.bmcl.2010.10.119Get rights and content

Abstract

In this study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 2-substituted 5-hydroxyindole-3-carboxylate derivatives as potent 5-LOX inhibitors with IC50 values ranging from 0.031 to 13.4 μM. Two datasets of same molecules were prepared with two different partial atomic charges; one with Gasteiger–Huckel and another with the ESPFIT charges obtained from the gaussian package. CoMFA and CoMSIA models were generated for both the datasets and the results were analysed. With regard to the non-cross validated r2 values (rncv2) and cross-validated q2 values (qcv2) of the resulting QSAR models, the dataset with ESPFIT charges yielded higher values; hence it was further used in the study. The CoMFA and CoMSIA models have been further validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of ten compounds. The predictive power of the CoMSIA model was higher than the CoMFA model, the high predictive r2 values of the test set reveals that the models prove to be useful tools for activity prediction of newly designed 5-LOX inhibitors. The ESPFIT-derived charges yielded better models than those based on charges calculated from Gasteiger–Huckel charges. We generated a homology model for human 5-LOX and identified the key residues at the binding site. The 3D-QSAR models were compared with the interactions at the active site to further elucidate the accuracy of the models. The data generated from 3D-QSAR study was used to design potential 5-LOX inhibitors.

Graphical abstract

In this Letter, CoMFA and CoMSIA were performed on a series of 2-substituted 5-hydroxyindole-3-carboxylate derivatives as potent 5-LOX inhibitors. The data generated from the present study will further help design and validate novel and potent 5-LOX inhibitors.

  1. Download : Download high-res image (59KB)
  2. Download : Download full-size image

Section snippets

Acknowledgments

We thank Centre for Modelling, Simulation and Design (CMSD), University of Hyderabad and Bioinformatics Infrastructure Facility, Dept. of Biotechnology, University of Hyderabad for permitting us to use the computational facilities. We duly acknowledge UGC for providing Dr. D. S. Kothari Postdoctoral fellowship to P. Aparoy.

References and notes (31)

  • A.R. Brash

    J. Biol. Chem.

    (1999)
  • P. Aparoy et al.

    Bioorg. Med. Chem. Lett.

    (2010)
  • L. Stahle et al.

    Prog. Med. Chem.

    (1988)
  • A. Golbraikh et al.

    J. Mol. Graphics Modell

    (2002)
  • R.A. Laskowski et al.

    J. Mol. Biol.

    (1993)
  • G. Jones et al.

    J. Mol. Biol.

    (1997)
  • P. Aparoy et al.

    J. Mol. Graphics Modell

    (2009)
  • C.D. Funk

    Science

    (2001)
  • S.M. Rapoport et al.

    Eur. J. Biochem.

    (1979)
  • E.M. Davidson et al.

    Ann. Rheum. Dis.

    (1983)
  • D. Nie et al.

    Cancer Metastasis Rev.

    (2001)
  • K.M. Anderson et al.

    Prostate

    (1998)
  • I.M. Avis et al.

    J. Clin. Invest.

    (1996)
  • D. Wang et al.

    Nat. Rev. Cancer

    (2010)
  • Y. Chen et al.

    Nat. Genet.

    (2009)
  • Cited by (26)

    • Combined computational approaches for developing new anti-Alzheimer drug candidates: 3D-QSAR, molecular docking and molecular dynamics studies of liquiritigenin derivatives

      2022, Heliyon
      Citation Excerpt :

      Therefore, before starting modeling, the most active compound (3d) (pIC50 = 5.59) was chosen as template structure, and then all remaining molecules were subjected to a molecular alignment process, based on their structural similarities to the template skeleton, by using the distill module available in SYBYL 2.1 software [17]. To identify the most important structural properties governing the biological activity of the studied compounds, 3D-QSAR models were developed by adopting Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) techniques [23, 24]. These techniques allow us to explore the effects of different molecular descriptors, including steric, electrostatic, hydrophobic, donor of hydrogen bonds and acceptor of hydrogen bonds, on biological activity [25].

    • Recent advances in the Nenitzescu indole synthesis (1990–2019)

      2021, Advances in Heterocyclic Chemistry
      Citation Excerpt :

      Several 5-hydroxyindoles and 5-hydroxybenzofurans substituted with imidazole rings obtained via Nenitzescu reaction revealed weak antimicrobial and anesthetic activity (1994PCJ103). Compounds with a 5-hydroxyindole skeleton formed from benzoquinones and enamines are potent inhibitors of enzymes such as 5-lipoxygenase, phospholipase A2 (PLA2s) and other enzymes that are implied in an inflammatory response of a wide range of diseases (1996JO9055, 2006JMC4327, 2009JMC3474, 2011BMCL456, 2011CBDD314, 2014EJMC492, 2014PLOe87708, 2016EJMC466, 2018EJMC946). The first selective PLA2s inhibitor, known as LY311727 (Scheme 72), was obtained starting from 5-hydroxyindole 420, which in turn was prepared by Nenitzescu reaction (1996JO9055).

    • QSAR classification-based virtual screening followed by molecular docking studies for identification of potential inhibitors of 5-lipoxygenase

      2018, Computational Biology and Chemistry
      Citation Excerpt :

      Several QSAR works (Babu et al., 2002; Eren et al., 2012) were performed in recent years with the aim of formulating an excellent predictive model which composed of common chemical features among a considerable number of known 5-LOX inhibitors. A number of these studies (Aparoy et al., 2011; Zheng et al., 2006) have used comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) as a tool to model the activity of 5-LOX inhibitors. Several other studies (Andrada et al., 2015; Ruiz et al., 2003) have used the conventional 2D QSAR methods such as Multiple Linear Regression (MLR), Principle Component Analysis (PCA) and Partial Least Square regression (PLS).

    • Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors

      2015, European Journal of Medicinal Chemistry
      Citation Excerpt :

      Energy minimizations were performed using Gasteiger-huckel charge and Tripos force field with a distance-dependent dielectric and the Powell conjugate gradient algorithm with convergence criterion of 0.05 kcal/mol [45]. Subsequently, all structures were aligned by the common substructure using “molecular alignment” [48,49] with the most active compound 5e was chosen as a template molecule (Fig. 8). For aligned training set, CoMFA steric and electrostatic fields were calculated at each lattice point with grid spacing value of 2.0 Å in all Cartesian directions.

    View all citing articles on Scopus
    View full text