Unsupervised 3D Ring Template Searching as an Ideas Generator for Scaffold Hopping:  Use of the LAMDA, RigFit, and Field-Based Similarity Search (FBSS) Methods

Abstract

Crystal structures taken from the Cambridge Structural Database were used to build a ring scaffold database containing 19 050 3D structures, with each such scaffold then being used to generate a centroid connecting path (CCP) representation. The CCP is a novel object that connects ring centroids, ring linker atoms, and other important points on the connection path between ring centroids. Unsupervised searching in the scaffold and CCP data sets was carried out using the atom-based LAMDA and RigFit search methods and the field-based similarity search method. The performance of these methods was tested with three different ring scaffold queries. These searches demonstrated that unsupervised 3D scaffold searching methods can find not only the types of ring systems that might be retrieved in carefully defined pharmacophore searches (supervised approach) but also additional, structurally diverse ring systems that could form the starting point for lead discovery programs or other scaffold-hopping applications. Not only are the methods effective but some are sufficiently rapid to permit scaffold searching in large chemical databases on a routine basis.

Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization

“…The concept of reducing chemical substructures to simpler nodes has also been used in 3D methods such as the centroid connecting path (CCP) representation 84. This method reduced rings to the 3D coordinates of their geometric centre, or centroid.…”

Searching Chemical Space with the Bayesian Idea Generator

“…The ability of an in-silico search method to identify a novel chemical series with the same activity as a given series is known as scaffold or chemotype hopping. ,− Chemotype jumping is desirable for a variety of reasons: the novel series might be easier to work on synthetically, might have fewer or at least different pharmacological risks, and/or might by free from intellectual property constraints. The Bayesian Idea Generator offers more chance of chemotype jumps compared to a 2D Tanimoto similarity search via three mechanisms:…”

Generation of New Synthetic Scaffolds Using Framework Libraries Selected and Refined via Medicinal Chemist Synthetic Expertise

“…An even broader application of this method is "lead hopping" using a pharmacophore derived from an active small molecule. 21 In order to exemplify application of the VFL method to this more general problem, we will show the steps in the entire process from the query definition, searching, hit validation, and finally the design of some new proposed templates. The first step is to prepare a query.…”