Scaffold Hopping by Fragment Replacement

Abstract

This work describes a data driven method for scaffold hopping by fragment replacement. A search database of scaffolds is created by cutting bonds of existing compounds in a combinatorial fashion. Three-dimensional structures of the scaffolds are then generated and made searchable based on the relative orientation of the broken bonds using an auxiliary index file. The retrieved scaffolds are ranked using volume overlap and electrostatic similarity scores. A similar approach has been used before in the program CAVEAT and others. The present work introduces a novel indexing scheme for the attachment vector geometry, which allows for fast searching. A scaffold shape descriptor is defined, which allows for queries with a single attachment vector (R-groups) and improves the shape similarity between the query and the suggested replacement fragments. The program, called Scaffold Hopping, is shown to retrieve relevant bioisosteric replacement scaffolds for a set of example queries in a reasonable time frame, making the program suitable to be used in drug design work.

One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

“…One possibility to realize the change required in the scaffold is isostericr eplacement of certain atomsi nt he structural core. [14] Thiss trategy has been successful for the development of new topoisomerase I( To pI)i nhibitors as potential an-ticancera gentsb yo ptimization of the binding to the TopI-DNA covalent complex, as well as form arketed drugs, for example,identification of Vardenafil by scaffold hopping from Sildenafil. [15][16][17] One of the most-popular isostericp airs, especially in compounds that possess ah eterocyclic scaffold, are CH and N. [15,16,18] This replacement is often linked to improved solubility and reduced lipophilicity,w hich we have already shown for the pyrido [3,4-c] [1,9]phenanthrolines 8.…”

Deep Generative Models for 3D Compound Design

“…Several traditional methods exist for linking fragments or replacing the core of a molecule. [24][25][26][27][28][29] Almost all methods rely on a database from which to select linkers. As a baseline with which to compare our method, we created a set of all linkers from the training data and sampled from this set, joining the linker in one of the two possible orientations at random.…”

“…22,23 Numerous computational methods have been proposed for fragment linking or scaffold hop-ping. [24][25][26][27][28][29] However, almost all methods published to date rely exclusively on a database of candidate fragments from which to select a linker, with the differences between approaches arising solely from how the database is searched, how the linked compounds are scored, or the contents of database itself. As a result, these methods are inherently constrained to a set of predetermined rules or examples, limiting exploration of chemical space.…”

A Bioisosteric and Scaffold Hopping Approach for the Design and Synthesis of Double Ring Replacement Analogues of 4‐Aryl‐4H‐Chromenes and in silico Tubulin Inhibitor Studies

“…The concept of bioisosteric replacement is based on the assumption that similar biological activity can be exerted by the compounds which are obtained by replacing a group with its isostere . Scaffold hopping refers to a type of bioisosteric replacement where the central core of a template‐chemical structure is replaced, while maintaining some of the essential features . Generally, the main aim of scaffold hopping is to discover equipotent compounds with different backbone that have enhanced biological activity and improved physicochemical properties than the compounds that are active against a preselected biological target.…”

“…[5] Scaffold hopping refers to a type of bioisosteric replacement where the central core of a template-chemical structure is replaced, while maintaining some of the essential features. [6][7][8][9] Generally, the main aim of scaffold hopping is to discover equipotent compounds with different backbone that have enhanced biological activity and improved physicochemical properties than the compounds that are active against a preselected biological target. The modifications of a templatechemical structure with desired biological activity may include ring replacement by heterocyclic ring.…”