Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach

Goracci, Laura; Buratta, Sandra; Urbanelli, Lorena; Ferrara, Giuseppina; Guida, Riccardo Di; Emiliani, Carla; Cross, Simon

doi:10.1016/j.ejmech.2014.12.028

Cited by 29 publications

(21 citation statements)

References 48 publications

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“…The FLAPpharm algorithm 39 was then used with the aim of building a robust pharmacophore model for HDAC6 catalytic inhibitors. This approach has been successfully used in the past for constructing a discriminating toxicophore model for phospholipidosis (PLD) inducers, for differentiating adenosine receptor subtypes, and recently for discovering inhibitors of a novel drug/proton antiporter 40 41 42 . In order to generate a pharmacophore by using the FLAPpharm approach, a minimum of three molecules is required 39 .…”

Section: Resultsmentioning

confidence: 99%

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Goracci

Deschamps

Randazzo

et al. 2016

Sci Rep

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The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.

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Section: Resultsmentioning

confidence: 99%

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Goracci

Deschamps

Randazzo

et al. 2016

Sci Rep

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“…Following this, the resulting alignment model is used to derive the common pharmacophore. The FLAPpharm pharmacophore can be described as a 'pseudomolecule', which is composed of common pharmacophoric interaction fields (PIFs), common atom-centred pseudopharmacophoric fields (pseudoPIFs) and common pharmacophoric points at the centroid of these pseudoPIFs, and can be used as a template for virtual screening in the FLAP software (Sirci et al, 2012;Goracci et al, 2014). FLAPpharm requires at least three active molecules for pharmacophore generation.…”

Section: Ic 50 Determination Of Selected Compounds For [ 3 H]-clonidimentioning

confidence: 99%

Pharmacophore‐based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line

Chapy

Goracci

Vayer

et al. 2015

British J Pharmacology

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Background and Purpose An influx drug/proton antiporter of unknown structure has been functionally demonstrated at the blood–brain barrier. This transporter, which handles some psychoactive drugs like diphenhydramine, clonidine, oxycodone, nicotine and cocaine, could represent a new pharmacological target in drug addiction therapy. However, at present there are no known drugs/inhibitors that effectively inhibit/modulate this transporter in vivo. Experimental Approach The FLAPpharm approach was used to establish a pharmacophore model for inhibitors of this transporter. The inhibitory potency of 44 selected compounds was determined against the specific substrate, [3H]‐clonidine, in the human cerebral endothelial cell line hCMEC/D3 and ranked as good, medium, weak or non‐inhibitor. Key Results The pharmacophore model obtained was used as a template to screen xenobiotic and endogenous compounds from databases [Specs, Recon2, Human Metabolome Database (HMDB), human intestinal transporter database], and hypothetical candidates were tested in vitro to determine their inhibitory capacity with [3H]‐clonidine. According to the transporter database, 80% of the proton antiporter inhibitor candidates could inhibit P‐glycoprotein/MDR1/ABCB1 and specificity is improved by reducing inhibitor size/shape and increasing water solubility. Virtual screening results using HMDB and Recon2 for endogenous compounds appropriately scored tryptamine as an inhibitor. Conclusions and Implications The pharmacophore model for the proton‐antiporter inhibitors was a good predictor of known inhibitors and allowed us to identify new good inhibitors. This model marks a new step towards the discovery of this drug/proton antiporter and will be of great use for the discovery and design of potent inhibitors that could potentially help to assess and validate its pharmacological role in drug addiction in vivo.

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“…[56] FLAP (Fingerprints for Ligands and Proteins) is av irtual screening algorithm developed and licensed by Molecular Discovery Ltd. (www.moldiscovery.com). Several VS campaigns have been successfully performed with FLAP and are reported in the literature, [69,70,[80][81][82][83][84][85] as well as binding mode prediction and rationalization. [86,87] Initially,t he approach uses the GRID force field to evaluate the type, strength and direction of the interactions that ac avity is capable of making.…”

Section: Methodsmentioning

confidence: 99%

Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case

et al. 2016

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Repurposing and repositioning drugs has become a frequently pursued and successful strategy in the current era, as new chemical entities are increasingly difficult to find and get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid and effective off-target identification and drug repurposing. Our method is based on the structural and chemical properties of protein binding sites, that is, the ligand image, encoded in the GRID molecular interaction fields (MIFs). Protein similarity is disclosed through the BioGPS algorithm by measuring the pockets' overlap according to which pockets are clustered. Co-crystallized and known ligands can be cross-docked among similar targets, selected for subsequent in vitro binding experiments, and possibly improved for inhibitory potency. We used human thymidylate synthase (TS) as a test case and searched the entire RCSB Protein Data Bank (PDB) for similar target pockets. We chose casein kinase IIα as a control and tested a series of its inhibitors against the TS template. Ellagic acid and apigenin were identified as TS inhibitors, and various flavonoids were selected and synthesized in a second-round selection. The compounds were demonstrated to be active in the low-micromolar range.

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Evaluating the risk of phospholipidosis using a new multidisciplinary pipeline approach

Cited by 29 publications

References 48 publications

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors

Pharmacophore‐based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line

Comparing Drug Images and Repurposing Drugs with BioGPS and FLAPdock: The Thymidylate Synthase Case

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