Pharmacophore-Based Screening and Identification of Novel Human Ligase I Inhibitors with Potential Anticancer Activity

Krishna, Shagun; Singh, Deependra Kumar; Meena, Sanjeev; Datta, Dipak; Siddiqi, Mohammad Imran; Banerjee, Dibyendu

doi:10.1021/ci5000032

Cited by 39 publications

(25 citation statements)

References 48 publications

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“…Of the thirty-one representative molecules only eight compounds could be purchased and tested for their ability to inhibit p38α. The results of the assays showed only four of the compounds to be active, resulting in a success rate of around 50%, similar to those reported in previous studies [25]. …”

Section: Resultssupporting

confidence: 88%

Identification of a Novel Inhibitory Allosteric Site in p38α

Gómez-Gutiérrez

Campos²,

Vega³

et al. 2016

PLoS ONE

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In the present study, we report the discovery of a novel allosteric inhibitory site for p38α, a subclass of the mitogen-activated protein kinases (MAPK) family. The putative site was discovered after inspection of the crystallographic structure of the p38α-MK2 complex. MK2 (MAPK-activated protein kinase 2) is an interesting protein playing a dual role as modulator and substrate of p38α. This intriguing behavior is due to the ability of the two proteins to form distinctive heterodimers when p38α is phosphorylated or not. We hypothesized that the regulatory action of MK2 is due to its capability to keep p38α in an inactive conformation and consequently, we investigated the atomic structure of the p38α-MK2 complex to understand such regulatory behavior at the molecular level. After inspection of the complex structure, two peptides designed from the MK2 regulatory loop in contact with p38α with sequences Tyr1-Ser2-Asn3-His4-Gly5-Leu6 (peptide-1) and [Phe0]-peptide-1 (peptide-2) in their zwitterionic form were investigated for their phosphorylation inhibitory capability in vitro. Since both peptides exhibited inhibitory capability of the p38α kinase mediated phosphorylation of MEF2A, in a subsequent step we pursued the discovery of small molecule peptidomimetics. For this purpose we characterized in detail the peptide-p38α interaction using molecular dynamics simulations, leading to the definition of a pharmacophore for the peptide-protein interaction. This hypothesis was used as query for a in silico screening, leading to the discovery of a fused ring compound with micromolar inhibitory activity. Site-directed mutagenesis studies support that the compound binds to the putative novel allosteric site in p38α.

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Section: Resultssupporting

confidence: 88%

Identification of a Novel Inhibitory Allosteric Site in p38α

Gómez-Gutiérrez

Campos²,

Vega³

et al. 2016

PLoS ONE

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“…The success rate was approximately one third of the molecules tested as previously found by other authors in similar studies [47]. Table 1 shows the structures as well as the antagonistic activity to the human bradykinin B2 receptor of a selected group of hits, disclosed to give support to the pharmacophore hypothesis developed in this work.…”

Section: Proof Of Conceptsupporting

confidence: 76%

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Lupala

Gómez-Gutiérrez

Pérez

2015

J Comput Aided Mol Des

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Abstract:Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a receptor upregulated during inflammation episodes or tissue trauma and B2 that is constitutively expressed in a variety of cell types. The goal of the present work is to carry out a structure-activity study of BK B2 antagonism, taking into account the stereochemical features of diverse non-peptide antagonists and the way these features translate into ligand anchoring points to complementary regions of the receptor, through the analysis of the respective ligand-receptor complex. For this purpose an atomistic model of the BK B2 receptor was built by homology modeling and subsequently refined embedded in a lipid bilayer by means of a 600 ns molecular dynamics trajectory. The average structure from the last hundred nanoseconds of the molecular dynamics trajectory was energy minimized and used as model of the receptor for docking studies. For this purpose, a set of compounds with antagonistic profile, covering maximal diversity were selected from the literature. Specifically, the set of compounds include Fasitibant, FR173657, Anatibant, WIN64338, Bradyzide, CHEMBL442294, and JSM10292. Molecules were docked into the BK B2 receptor model and the corresponding complexes analyzed to understand ligand-receptor interactions. The outcome of this study is summarized in a 3D pharmacophore that explains the observed structureactivity results and provides insight into the design of novel molecules with antagonistic profile. To prove the validity of the pharmacophore hypothesized a virtual screening process was also carried out. The pharmacophore was used as query to identify new hits using diverse databases of molecules. The results of this study revealed a set of new hits with structures not connected to the molecules used for pharmacophore development. A few of these structures were purchased and tested. The results of the binding studies show about a 33% success rate with a correlation between the number of pharmacophore points fulfilled and their antagonistic potency. Some of these Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationstructures are disclosed in the present work.Response to Reviewers: We sincerely appreciate the involvement of reviewer #1 and are deeply obliged. The reviewer was right in pointing the distortion of the ring and the amide in Figure 8 that has now been fixed in the revised version of Figure 8. We have also modified the viewpoint of Figure 9 to clearly show the protonation status of the terminal amine that was unfortunately hidden in the previous version of Figure 9 this study is summarized in a 3D pharmacophore that explains the observed structure-activity results and provides insight into the design of novel molecules with antagonistic profile. ...

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“…Since the initial identification of DNA ligase inhibitors by a structure-based approach (18,26), there have been several reports describing LigI inhibitors using computer modelling and derivatives of the original DNA ligase inhibitors (49–51). While these studies have shown that the inhibitors have activity against LigI in vitro, their affinity and selectivity appears to be less than that of L82-G17.…”

Section: Discussionmentioning

confidence: 99%

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

et al. 2017

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In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. Previously small molecule inhibitors of human DNA ligases were identified using a structure-based approach. Three of these inhibitors, L82, a DNA ligase I (LigI)-selective inhibitor, and L67, an inhibitor of LigI and DNA ligases III (LigIII), and L189, an inhibitor of all three human DNA ligases, have related structures that are composed of two 6-member aromatic rings separated by different linkers. Here we have performed a structure-activity analysis to identify determinants of activity and selectivity. The majority of the LigI-selective inhibitors had a pyridazine ring whereas the LigI/III- and LigIII-selective inhibitors did not. In addition, the aromatic rings in LigI-selective inhibitors had either arylhydrazone or acylhydrazone, but not vinyl linkers. Among the LigI-selective inhibitors, L82-G17 exhibited increased activity against and selectivity for LigI compared with L82. Notably. L82-G17 is an uncompetitive inhibitor of the third step of the ligation reaction, phosphodiester bond formation. Cells expressing DNA ligase I were more sensitive to L82-G17 than isogenic LIG1 null cells. Furthermore, cells lacking nuclear LigIIIα, which can substitute for LigI in DNA replication, were also more sensitive to L82-G17 than isogenic parental cells. Together, our results demonstrate that L82-G17 is a LigI-selective inhibitor with utility as a probe of the catalytic activity and cellular functions of LigI and provide a framework for the future design of DNA ligase inhibitors.

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Pharmacophore-Based Screening and Identification of Novel Human Ligase I Inhibitors with Potential Anticancer Activity

Cited by 39 publications

References 48 publications

Identification of a Novel Inhibitory Allosteric Site in p38α

Identification of a Novel Inhibitory Allosteric Site in p38α

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Structure-activity relationships among DNA ligase inhibitors: Characterization of a selective uncompetitive DNA ligase I inhibitor

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