Learning from our mistakes: The ‘unknown knowns’ in fragment screening

Abstract

In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening.

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

“…Since all of these methods have been extensively reviewed previously 13,16 here we focus only on compound library related issues such as assay sensitivity (i.e., the ability to detect weak hits), specificity (i.e., the ability to discriminate between separate binding events), throughput and hit rate ( Table 1). The propensity for false positives / false negatives in particular can be operator-dependent and even subjective and depends upon a definition of "hit."…”

“…13 Additionally, fragment libraries will typically be subjected to extensive initial and ongoing quality control (QC) analyses under conditions relevant to both the storage and screening of the samples. These should include quantitative assessments of the purity, identity, stability and solubility of the fragments, together with more specific analyses such as the aggregation properties of the fragments.…”

A Novel High Throughput Virtual Screening Protocol to Discover New Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

“…18) To ensure the compound identity, compound 9 was resynthesized according to Chart 1, in addition to synthetic feasibility check for future chemistry elaboration. The resynthesized compound 9 has the same IC 50 value of 8.8 µM as the purchased one.…”

HPLC Biogram Analysis: A Powerful Tool Used for Hit Confirmation in Early Drug Discovery

“…The process starts with a list of compounds selected by early phase discovery program working groups for further evaluation by biogram analysis, following the usual hit triaging steps involving potency criteria, selectivity, and chemotype tractability. The compound list, typically ranging from 10 …”