Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization

Abstract

Bioisosteric replacement and scaffold hopping are twin methods used in drug design to improve the synthetic accessibility, potency and drug like properties of a compound and to move into novel chemical space. Bioisosteric replacement involves swapping functional groups of a molecule with other functional groups that have similar biological properties. Scaffold hopping is the replacement of the core framework of a molecule with another scaffold that will improve the properties of the molecule or to find similar potent compounds that exist in novel chemical space. This review outlines the key concepts, importance and challenges of both methods using examples and comparisons of techniques available for finding bioisosteric replacements and scaffold hops. There are many methods available for bioisosteric replacement and scaffold hopping, all with their own advantages and disadvantages. Drug design projects would benefit from a combination of these methods to retrieve diverse and complimentary results. Continuing progress in these fields will allow further validation of both methods as well as the accumulation of knowledge on bioisosteres and possible scaffold replacements.

Chemoinformatics at the University of Sheffield 2002–2014

“…[35][36] The advantages of group fusion were greatest when searching for structurally diverse sets of bioactive molecules, suggesting its use in the scaffoldhopping and bioisostere studies that are of particular importance in the lead-discovery stage of drug research. [37] Since the initial Sheffield studies, the group fusion approach has been widely adopted.…”

Case Study 1: Scaffold Hopping for T‐Type Calcium Channel and Glycine Transporter Type 1 Inhibitors

“…The first generation of T-type Ca 2þ channel inhibitors 1-3 were drugs designed for other targets (antiepileptic, antihypertensive, and antipsychotics), but ancillary pharmacology studies indicated weak inhibition of T-type Ca 2þ channels ( Figure 16.1); thus, these tools lacked the potency and selectivity necessary for target validation of T-type Ca 2þ channel inhibition [27][28][29][30][31][32][33][34][35][36][37][38]. 1) While these tools provided little in terms of our understanding of T-type Ca 2þ channels, they did provide evidence that inhibition of T-type Ca 2þ channels in man was well tolerated upon both acute and chronic dosing with 1-3. As evidenced by the known prior art with 1-3, T-type Ca 2þ channels fit well within the MLSCN/MLPCN mandate, and therefore a T-type Ca 2þ channel highthroughput screen (HTS) was performed in 2008 [38].…”

“…As evidenced by the known prior art with 1-3, T-type Ca 2þ channels fit well within the MLSCN/MLPCN mandate, and therefore a T-type Ca 2þ channel highthroughput screen (HTS) was performed in 2008 [38]. 1) The screen was a kinetic assay utilizing HEK293 cells expressing the Ca v 3.2 channel against an 111 000 member compound library measuring calcium fluorescence. After counterscreens of the 4246 hits, only 1 hit remained that was both active as a T-type Ca 2þ channel antagonist and selective versus L-and N-type channels, a disubstituted 1,3,4-oxadiazole 4 (Ca v 3.2 IC 50 ¼ 2.5 mM) [38].…”

Bioisosterism in Medicinal Chemistry

“…Once a lead molecule has been identified, the medicinal chemist is faced with the considerable challenge of making small, defined changes to an identified core structure (also chemotype or scaffold) by the addition or substitution of functional groups to test specific hypotheses. While the challenge of scaffold hopping (the replacement of the functional or specific exit geometries of a molecular scaffold) is important, this challenge will only be considered as a subset of bioisosteric replacement in this book [14][15][16][17][18].…”