title: Computer-aided design of fragment mixtures for NMR-based screening.
abstract: Fragment-based drug discovery is widely applied both in industrial and in academic screening programs. Several screening techniques rely on NMR to detect binding of a fragment to a target. NMR-based methods are among the most sensitive techniques and have the further advantage of yielding a low rate of false positives and negatives. However, NMR is intrinsically slower than other screening techniques; thus, to increase throughput in NMR-based screening, researchers often assay mixtures of fragments, rather than single fragments. Herein we present a fast and straightforward computer-aided method to design mixtures of fragments taken from a library that have minimized NMR signal overlap. This approach enables direct identification of one or several active fragments without the need for deconvolution. Our approach entails encoding of NMR spectra into a computer-readable format that we call a fingerprint, and minimizing the global signal overlap through a Monte Carlo algorithm. The scoring function used favors a homogenous distribution of the global signal overlap. The method does not require additional experimental work: the only data required are NMR spectra, which are generally recorded for each compound as a quality control measure before its insertion into the library.
authors.affiliation: Design, Synthesis and Structure of Peptides and Proteins, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Arroyo
authors.forename: Michael
authors.initials: M
authors.lastname: Goldflam
authors.forename: Miguel
authors.initials: M
authors.lastname: Feliz
authors.forename: Ignasi
authors.initials: I
authors.lastname: Belda
authors.forename: Ernest
authors.initials: E
authors.lastname: Giralt
mesh_terms: D000465:Algorithms; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008279:Magnetic Resonance Imaging; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013696:Temperature; D014584:User-Computer Interface
chemical_list: D054852:Small Molecule Libraries