2009
DOI: 10.1007/978-1-60761-274-2_7
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Knowledge-Based Virtual Screening: Application to the MDM4/p53 Protein–Protein Interaction

Abstract: Chemogenomics knowledge-based drug discovery approaches aim to extract the knowledge gained from one target and to apply it for the discovery of ligands and hopefully drugs of a new target which is related to the parent target by homology or conserved molecular recognition. Herein, we demonstrate the potential of knowledge-based virtual screening by applying it to the MDM4-p53 protein-protein interaction where the MDM2-p53 protein-protein interaction constitutes the parent reference system; both systems are po… Show more

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Cited by 23 publications
(19 citation statements)
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“…In fact it has been reported over and over that PPI modulator identification is challenging with today's HTS libraries. 188 On the other hand PPIs sometimes are suitable for small molecule binding especially in the presence of deep and rather small binding grooves. For example PPIs targetable by small molecules have been classified by the dimensions and electrostatics of their interfaces.…”
Section: Mcrs By Target Classmentioning
confidence: 99%
“…In fact it has been reported over and over that PPI modulator identification is challenging with today's HTS libraries. 188 On the other hand PPIs sometimes are suitable for small molecule binding especially in the presence of deep and rather small binding grooves. For example PPIs targetable by small molecules have been classified by the dimensions and electrostatics of their interfaces.…”
Section: Mcrs By Target Classmentioning
confidence: 99%
“…Based on MDM2-p53 interactions as template, this approach was applied to the MDM4-p53 complex, where combination of virtual screening strategies resulted in unique compounds with varying degrees of selectivity for both MDM2-p53 and MDM4-p53 systems [99]. …”
Section: Discovery Of Inhibitors Targeting the P53-mdm2-mdmx Loopmentioning
confidence: 99%
“…Following a procedure previously published which involved a combination of several 2D and 3D virtual screening methods, around 50,000 compounds from the Novartis compound collection were selected for testing in our p53-MDM2 program. 9 From this effort, compound 1 (Table 1) was identified as an interesting hit inhibiting the p53-MDM2 interaction with an IC 50 value of 0.54 lM in our TR-FRET biochemical assay and showing a weak anti proliferative activity of 16.5 lM at the cellular level. 10,11 Compound 1 was considered to be an attractive starting point for further exploration.…”
Section: Introductionmentioning
confidence: 99%