title: Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors.
abstract: The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.
authors.affiliation: INSERM, U973, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Lagorce
authors.affiliation: CNRS UMR7275, Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, Valbonne, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Douguet
authors.affiliation: INSERM, U973, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.affiliation: INSERM, U973, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D055808:Drug Discovery / Q000379:methods; D004355:Drug Stability; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007700:Kinetics; D011485:Protein Binding / Q000187:drug effects*; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution