|
|
|
|
|
|
|
|
| Tudor Oprea, Univ. New Mexico |
|
|
The Physical basis for the Rule of Five
Tudor I. Oprea, University of New Mexico School of Medicine
Tudor I. Oprea (1), Scott Boyer (2), and Igor Tetko (3)
(1) Division of Biocomputing, UNM School of Medicine, MSC 11 6145, Albuquerque NM 87131-0001, USA
(2) Safety Assessment, Astrazeneca R&D Molndal, SE-431 83 Mölndal, Sweden
(3) München Information Center for Protein Sequences, GSF, Germany
Our understanding of the quality of leads for drug discovery rests on mining the known bioactivity and medchem spaces. Such sources are the WOMBAT database [1], which contains over 136,000 unique chemicals and 307,000 biological activities. A derivative database related to clinical pharmacokinetics is WOMBAT-PK (WB-PK) [2]. WOMBAT-PK 2006 contains 935 drugs with multiple human ADME/Tox endpoints: > 750 oral bioavailability and half-life data, > 700 plasma protein binding and volume of distribution (steady state) values, > 500 total clearance, non-renal clearance and maximum recommended therapeutic daily dose values, etc. Matching clinical data with calculated properties, one can gain better insights for lead discovery. The relationship between the Maximum Recommended Therapeutic (daily) Dose, MRTD, its value corrected for the fraction unbound, MRTD_U, and the partition coefficients (clogP and LogD74) will be discussed. These two parameters provide a physical basis to the Lipinski "Rule of five".
* the talk will explain the importance of property filtering in lead discovery
* it provides simple guidelines for computed property cut-off values
* it will discuss the importance of multi-parametric predictions to assist decision-makers in virtual and biomolecular screening
[1] Olah M, et al. WOMBAT: World of Molecular Bioactivity, in Chemoinformatics in Drug Discovery. Oprea TI (Ed), Wiley-VCH, New York, 2005, pp. 223-239.
[2] WOMBAT and WOMBAT-PK are available from http://www.sunsetmolecular.com
|
|
|
|
|
|
|
|
|
|
|
