Methods for Effective Virtual Screening and Scaffold-Hopping in Chemical Compounds

Abstract

Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. AbstractMethods that can screen large databases to retrieve a structurally diverse set of compounds with desirable bioactivity properties are critical in the drug discovery and development process. This paper presents a set of such methods, which are designed to find compounds that are structurally different to a certain query compound while retaining its bioactivity properties (scaffold hops). These methods utilize various indirect ways of measuring the similarity between the query and a compound that take into account additional information beyond their structure-based similarities. Two sets of techniques are presented that capture these indirect similarities using approaches based on automatic relevance feedback and on analyzing the similarity network formed by the query and the database compounds. Experimental evaluation shows that many of these methods substantially outperform previously developed approaches both in terms of their ability to identify structurally diverse active compounds as well as active compounds in general.

Trends in Chemical Graph Data Mining

“…Recently, a set of techniques to improve the scaffold-hopping performance have been introduced that are based on measuring the similarity between the query and a compound by taking into account additional information beyond their descriptor-space-based representation ( [54], [56]). These methods are motivated by the observation that if a query compound is structurally similar to a database compound and is structurally similar to another database compound , then and could be considered as being similar or related even though they may have zero or very low direct similarity.…”

“…For the problem of scaffold-hopping, the similarity between a pair of nodes is determined as a function of the intersection of their adjacency lists ( [54], [56]), which takes into account all two-edge paths connecting these nodes. Specifically, the similarity between and with respect to graph is given by…”