3D 化合物库（用于HTS）

If a dramatic change of the molecular shape is necessary, it would require a lot of activation energy, making such a compound unsuitable as a drug. In contrast, if the molecule is already in “bioactive conformation” (suitable shape for binding), it is more likely to bind strongly and be a good drug. Non-planar screening compounds with diverse and well-developed 3D shapes have become the most attractive ones on the market for HTS in the last few years. Higher three-dimensionality (3D) of hit compounds has been shown to correlate with their successful passage of various clinical development stages.

Library Design

3D-shaped Diversity Compound Library

The so-called “3D-shapeless” is defined by the plane of best fit (PBF) or principal moments of inertia (PMI) parameters thresholds, which at the moment are the best metrics that describe the shape of the molecule. Detailed analysis of publications on this subject enabled us to establish a set of criteria that allow evaluating the 3D diversity of the molecules. These cut-offs with respect to physicochemical parameters were applied to the Life Chemicals HTS Compound Collection to result in a selection of over 22,700 drug-like screening compounds.

3D-pharmacophore-based Diversity Library

First, PAINS filters together with Life Chemicals toxicophore and undesired functionalities filters developed in-house, were applied to the Life Chemicals HTS Compound Collection. A 3D conformation was generated for each molecule, after that three of the most different 3-centered pharmacophore hypotheses were constructed, focusing on physicochemical parameters (HBA, HBD, etc. points). The most diverse virtual hits were then selected from each pharmacophore pool, which covered a broad chemical space. In total, over 8,700 structurally diverse screening compounds based on privileged 3D scaffolds were selected in accordance with these pharmacophore hypotheses.