Application of Negative Design To Design a More Desirable Virtual Screening Library

Negative
design is a group of virtual screening methods that aims
at weeding out compounds with undesired properties during the early
stages of drug development. These methods are mainly designed to predict
three important types of pharmacological properties: drug-likeness,
frequent hitters, and toxicity. In order to achieve high screening
efficiency, most negative design methods are physicochemical property-based
and/or substructure-based rules or filters. Such methods have advantages
of simplicity and good interpretability, but they also suffer from
some defects such as inflexibility, discontinuity, and hard decision-making.
In this review, the advances in negative design for the evaluations
of drug-likeness, frequent hitters, and toxicity are outlined. In
addition, the related Web servers and software packages developed
recently for negative design are summarized. Finally, future research
directions in this field are discussed.