Library Enhancement through the Wisdom of Crowds

Abstract

We present a novel approach for enhancing the diversity of a chemical library rooted on the theory of the wisdom of crowds. Our approach was motivated by a desire to tap into the collective experience of our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds for acquisition were screened using various structural and property filters in order to eliminate clearly nondrug-like matter. (2) The remaining compounds were clustered together with our in-house collection using a novel fingerprint-based clustering algorithm that emphasizes common substructures and works with millions of molecules. (3) Clusters populated exclusively by external compounds were identified as "diversity holes," and representative members of these clusters were presented to our global medicinal chemistry community, who were asked to specify which ones they liked, disliked, or were indifferent to using a simple point-and-click interface. (4) The resulting votes were used to rank the clusters from most to least desirable, and to prioritize which ones should be targeted for acquisition. Analysis of the voting results reveals interesting voter behaviors and distinct preferences for certain molecular property ranges that are fully consistent with lead-like profiles established through systematic analysis of large historical databases.

The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

“…Of the 685 compounds tested, 459 showed an EC 50 <4 µM, which underscores the inherent accuracy of the original screening data. A final collection of 400 were selected by a ‘wisdom of the crowd’ approach using experienced medicinal chemists [28].…”

mQC: A Heuristic Quality-Control Metric for High-Throughput Drug Combination Screening

“…In particular we based the development of the QC metric on a crowd-sourced assessment of response matrix quality. The use of crowd-sourced assessments of “quality” and other abstract descriptors has precedents14151617. For example, Lajiness et al 18.…”

The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation

“…Hack et al . reported an analogous study that sought to enhance the diversity of the Johnson & Johnson corporate structure database; they found that whilst there were considerable differences between individual chemists a fair level of consistency could be achieved using a wisdom-of-crowds approach [11]. This technique was also used by Oprea et al .…”