| Title | Property distribution in the chemical space of PPAR-γ agonists: evaluation of drug-like characteristics | ||
| Authors | C. Giaginis1,2, A. Zira1,2, S. Theocharis2 and A.Tsantili-Kakoulidou1
1. Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Athens, Greece 2. Department of Forensic Medicine and Toxicology, Medical School, University of Athens, Greece |
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| Citation | Giaginis, C., Zira, A., Theocharis, S., Tsantili-Kakoulidou, A.: Property distribution in the chemical space of PPAR-γ agonists: evaluation of drug-like characteristics, Epitheorese Klin. Farmakol. Farmakokinet. 22(2): 366-368 (2008) | ||
| Publication Date | 23-25 May 2008 | ||
| Full Text Language | English | ||
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| Keywords | ADME/Tox, druglike properties, PPAR-γ agonists, rule of 5, lipophilicity. | ||
| Other Terms | Review article | ||
| Summary | High-throughput screening of absorption, distribution, metabolism, elimination/toxicology (ADME/Tox) characteristics has been introduced in the early steps of Drug Design as an emergent demand to reduce attrition rate of drug candidates due to poor pharmacokinetic profiles, as well as toxicity side effects. In this aspect, certain physicochemical and molecular properties have been considered as in silico predictors of oral bioavailability, while tolerant cut off values or ranges have been proposed to reflect druglike characteristics. In the present study, evaluation of druglikeness was performed in the case of PPAR-γ agonists, a category of chemical compounds with increasing interest as orally administrated drug candidates against diabetes mellitus. For this purpose, a large data set of 1152 relevant compounds available in literature was compiled and explored in respect to several physicochemical properties. Lipophilicity expressed as logP (or logD7.4), the number of hydrogen bond acceptor/donor sites (HBA/HBA) and molecular weight (MW) implemented in ‘Lipinski’s rule of five’ (ROF) were calculated by widely recognized software packages. The distribution of the above properties was established and evaluated in respect to the proposed cut off values or ranges. Violations concerning excess logP and MW were found for a significant number of compounds, while HBA and HBA did not exceed the proposed cut off values. The same analysis was repeated discriminating the data set into two groups according to activity levels expressed by PPAR-γ gene transactivation (pEC50 > 7 and pEC50 ≤ 7) and the relevant physicochemical characteristics were assigned to each group. A score in violation of ROF = 2 was found for 40% of the active compounds. This information is important and can be incorporated in a more holistic approach for future design of PPAR-γ agonists with improved molecular properties and therefore enhanced chance to success within clinical development. | ||
| References | 1. Kerns E.H.: High throughput physicochemical profiling for drug discovery. J. Pharm. Sci. 90: 1838-1858 (2001)
2. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J.: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivey Rev. 23: 3-25 (1997) 3. Muegge I.: Selection criteria for drug-like compounds. Med. Res. Rev. 23: 302-321 (2003) 4. Willson T.M., Brown P.J., Strenbach D.D., Henke B.R.: The PPARs: From orphan receptors to drug discovery. J. Med. Chem. 43: 527-550 (2000) 5. Oprea T.I.: Property distribution of drug-related chemical databases. J. Comput. Aided Mol. Des. 14: 251-264 (2000) 6. Oprea T.I., Davis A.M., Teague S.J., Leeson P.D.: Is there a difference between leads and drugs? A historical perspective. J. Chem. Inf. Comput. Sci. 41: 1308-1315 (2001) |
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| Relative Papers | |||
Online ISSN 1011-6575
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Articles published in this Journal are Indexed or Abstracted in: • Chemical Abstracts • Elsevier’s Bibliographic Databases: Scopus, EMBASE, EMBiology, Elsevier BIOBASE SCImago Journal and Country Rank Factor
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