Prediction and mechanistic interpretation of human oral drug absorption using MI-QSAR analysis.
Membrane-interaction [MI]-QSAR analysis, which includes descriptors explicitly derived from simulations of solutes [drugs] interacting with phospholipid membrane models, was used to construct QSAR models for human oral intestinal drug absorption. A data set of 188 compounds, which are mainly drugs, was divided into a parent training set of 164 compounds and a test set of 24 compounds. Stable, but not highly fit [R2 = 0.68] MI-QSAR models could be built for all 188 compounds. However, the relatively large number [47] of drugs having 100% absorption, as well as all zwitterionic compounds [11], had to be eliminated from the training set in order to construct a linear five-term oral absorption diffusion model for 106 compounds which was both stable [R2 = 0.82, Q2 = 0.79] and predictive given the test set compounds were predicted with nearly the same average accuracy as the compounds of the training set. Intermolecular membrane-solute descriptors are essential to building good oral absorption models, and these intermolecular descriptors are displaced in model optimizations and intramolecular solute descriptors found in published oral absorption QSAR models. A general form for all of the oral intestinal absorption MI-QSAR models has three classes of descriptors indicative of three thermodynamic processes: (1) solubility and partitioning, (2) membrane-solute interactions, and (3) flexibility of the solute and/or membrane. The intestinal oral absorption MI-QSAR models were compared to MI-QSAR models previously developed for Caco-2 cell permeation and for blood-brain barrier penetration. The MI-QSAR models for all three of these ADME endpoints share several common descriptors, and suggest a common mechanism of transport across all three barriers. A further analysis of these three types of MI-QSAR models has been done to identify descriptor-term differences across these three models, and the corresponding differences in thermodynamic transport behavior of the three barriers.
Iyer
Manisha
M
Laboratory of Molecular Modeling and Design, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612-7231, USA.
Tseng
Y J
YJ
Senese
C L
CL
Liu
Jianzhong
J
Hopfinger
A J
AJ
D000284:Administration, Oral; D002463:Cell Membrane Permeability; D005544:Forecasting; D006801:Humans; D007408:Intestinal Absorption; D008567:Membranes, Artificial; D008958:Models, Molecular; D015394:Molecular Structure; D019999:Pharmaceutical Solutions / Q000737:chemistry* / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
D008567:Membranes, Artificial; D019999:Pharmaceutical Solutions; D010743:Phospholipids