Statistical molecular design of peptoid libraries

Anna Linusson, Svante Wold
Research Group for Chemometrics, Department of Organic Chemistry, Umeå University, S-901 87 Umeå, Sweden

Bo Nordén
Astra Hässle AB, S-431 83 Mölndal, Sweden

Abstract
Statistical experimental design provides an efficient approach for selecting the building blocks to span the structural space and increase the information content in a combinatorial library. A set of renin-inhibitors, hexapeptoids, is used to illustrate the approach. Multivariate quantitative structure-activity relationships (MQSARs) were developed relating renin inhibition to the peptoid sequences variation, parametrized by the z-scales. By using the information from the models, the number of building block sets could be reduced from six to three. Using a statistical molecular design (SMD) reduces the number of compounds from more than 100 000 down to 90. A second SMD was used for comparison, based on less prior knowledge. This gave a reduction from over 2 billion to 120 compounds.

Keywords
combinatorial chemistry, D-optimal design, PCA, peptoid libraries, PLS, QSAR, statistical molecular design