Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

• Published in: Journal of computer-aided molecular design Vol. 25; no. 7; pp. 621 - 636
• Main Authors: Lau, Wan F., Withka, Jane M., Hepworth, David, Magee, Thomas V., Du, Yuhua J., Bakken, Gregory A., Miller, Michael D., Hendsch, Zachary S., Thanabal, Venkataraman, Kolodziej, Steve A., Xing, Li, Hu, Qiyue, Narasimhan, Lakshmi S., Love, Robert, Charlton, Maura E., Hughes, Samantha, van Hoorn, Willem P., Mills, James E.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.07.2011; Springer Nature B.V
• Subjects: Animal Anatomy; Binding; Binding Sites; Chemical reactions; Chemistry; Chemistry and Materials Science; Combinatorial Chemistry Techniques - methods; Complexity; Computer Applications in Chemistry; Crystallography, X-Ray; Design engineering; Drug Discovery; Drug Industry; Drugs; Fragmentation; High-Throughput Screening Assays; Histology; Humans; Libraries; Ligands; Magnetic Resonance Spectroscopy; Molecular structure; Morphology; Peptide Fragments - chemistry; Peptide Library; Pharmaceutical sciences; Physical Chemistry; Protein Conformation; Proteins - chemistry; R&D; Research & development; Screening; Library design; Fragment screening; Chemical space; Chemical diversity; Fragment based drug design
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-011-9434-0

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM–mM hits and the uniqueness of hits at weak binding affinities for these targets.