A topological sub-structural approach for predicting human intestinal absorption of drugs.
The human intestinal absorption (HIA) of drugs was studied using a topological sub-structural approach (TOPS-MODE). The drugs were divided into three classes according to reported cutoff values for HIA. "Poor" absorption was defined as HIA < or =30%, "high" absorption as HIA > or =80%, whereas "moderate" absorption was defined between these two values (30% < HIA < 79%). Two linear discriminant analyses were carried out on a training set of 82 compounds. The percentages of correct classification, for both models, were 89.02%. The predictive power of the models were validated by three test: a leave-one-out cross validation procedure (88.9% and 87.9%), an external prediction set of 127 drugs (92.9% and 80.31%) and a test set of 109 oral drugs with bioavailability values reported (93.58% and 91.84%). Finally, positive and negative sub-structural contributions to the HIA were identified and their possibilities in the lead generation and optimization process were evaluated.
Pérez
Miguel Angel Cabrera
MA
Department of Drug Design, Center of Chemical Bioactive, Central University of Las Villas, Santa Clara, 54830 Villa Clara, Cuba. migue@gammu.com
Sanz
Marival Bermejo
MB
Torres
Liliana Ramos
LR
Avalos
Ricardo Grau
RG
González
Maykel Pérez
MP
Díaz
Humberto González
HG
D001682:Biological Availability; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations