In silico modelling of permeation enhancement potency in Caco-2 monolayers based on molecular descriptors and random forest.
| Title: | In silico modelling of permeation enhancement potency in Caco-2 monolayers based on molecular descriptors and random forest. |
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| Authors: | Welling SH; Global Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark; Technical University of Denmark, DTU Compute, 2800 Kgs. Lyngby, Denmark.; Clemmensen LK; Technical University of Denmark, DTU Compute, 2800 Kgs. Lyngby, Denmark.; Buckley ST; Global Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark.; Hovgaard L; Global Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark.; Brockhoff PB; Technical University of Denmark, DTU Compute, 2800 Kgs. Lyngby, Denmark.; Refsgaard HH; Global Research, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. Electronic address: hare@novonordisk.com. |
| Source: | European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V [Eur J Pharm Biopharm] 2015 Aug; Vol. 94, pp. 152-9. Date of Electronic Publication: 2015 May 21. |
| Publication Type: | Journal Article; Validation Study |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 9109778 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3441 (Electronic) Linking ISSN: 09396411 NLM ISO Abbreviation: Eur J Pharm Biopharm Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Science; Original Publication: Stuttgart : Wissenschaftliche Verlagsgesellschaft, c1991- |
| MeSH Terms: | Computer Simulation* ; Models, Chemical*; Intestinal Absorption/*drug effects ; Intestinal Mucosa/*drug effects ; Surface-Active Agents/*chemistry ; Surface-Active Agents/*pharmacology; Intestinal Mucosa/metabolism ; Surface-Active Agents/classification ; Technology, Pharmaceutical/methods ; Caco-2 Cells ; Electric Impedance ; Humans ; Molecular Structure ; Permeability ; Quantitative Structure-Activity Relationship ; Reproducibility of Results |
| Abstract: | Structural traits of permeation enhancers are important determinants of their capacity to promote enhanced drug absorption. Therefore, in order to obtain a better understanding of structure-activity relationships for permeation enhancers, a Quantitative Structural Activity Relationship (QSAR) model has been developed. The random forest-QSAR model was based upon Caco-2 data for 41 surfactant-like permeation enhancers from Whitehead et al. (2008) and molecular descriptors calculated from their structure. The QSAR model was validated by two test-sets: (i) an eleven compound experimental set with Caco-2 data and (ii) nine compounds with Caco-2 data from literature. Feature contributions, a recent developed diagnostic tool, was applied to elucidate the contribution of individual molecular descriptors to the predicted potency. Feature contributions provided easy interpretable suggestions of important structural properties for potent permeation enhancers such as segregation of hydrophilic and lipophilic domains. Focusing on surfactant-like properties, it is possible to model the potency of the complex pharmaceutical excipients, permeation enhancers. For the first time, a QSAR model has been developed for permeation enhancement. The model is a valuable in silico approach for both screening of new permeation enhancers and physicochemical optimisation of surfactant enhancer systems.; (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Contributed Indexing: | Keywords: Caco-2; Permeation enhancers; QSAR; Random forest; Surfactants |
| Substance Nomenclature: | 0 (Surface-Active Agents) |
| Entry Date(s): | Date Created: 20150526 Date Completed: 20160517 Latest Revision: 20191210 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.ejpb.2015.05.012 |
| PMID: | 26004819 |
| Database: | MEDLINE |
Journal Article; Validation Study