Topological Fingerprints as an Aid in Finding Structural Patterns for LRRK2 Inhibition. Issue 4 (11th March 2014)

• Record Type: Journal Article
• Authors: Kahn, Iiris; Lomaka, Andre; Karelson, Mati
• Is Part Of: Molecular informatics. Volume 33:Issue 4(2014:Apr.)
• Page Start: 269
• Page End: 275
• Publication Date: 2014-03-11
• Subjects: Cheminformatics -- Periodicals; QSAR (Biochemistry) -- Periodicals; Structure-activity relationships (Biochemistry) -- Periodicals; Drugs -- Structure-activity relationships -- Periodicals; 615.19
• DOI: 10.1002/minf.201300057
• Languages: English
• ISSNs: 1868-1743

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Multiplet‐based fingerprint mapping has been used to analyse the relationship between the structural features of potential drug candidates and the enzyme LRRK2 inhibition expressed as the inhibition constant (p<italic>K</italic>_i). For 198 structurally diverse compounds 4195 dimensional fingerprints were generated and mathematically manipulated using partial least squares (PLS) regression. A variation of PLS‐BETA technique was developed for the reduction of noise by eliminating excess variables that resulted in a 636 dimensional fingerprint related to p<italic>K</italic>_i. The QSAR model for the training set of 170 compounds (<italic>R</italic>²=0.87, <italic>Q</italic>²=0.77 and <italic>SDEC</italic>=0.42) had four latent variables (PLS components) and it was validated by the external test set of 28 compounds (<italic>Q</italic>_ext²=0.63). The proposed model of LRRK2 inhibitory activity can be helpful in designing focused libraries enriched in LRRK2 inhibitors and identifying new active chemotypes in compound databases.</p> </abstract>