NeBULA: a web-based novel drug design platform for up-to-date bioisosteric replacement

NeBULA uses SMARTS reactions to extract bioisosteric replacement pairs from extensive medicinal chemistry literature, based on experimental data. • Systematically collected and organized bioisosteric replacements from the latest medicinal chemistry literature. • Developed an optimization algorithm that ensures product molecular integrity via SMARTS-based reaction replacements. • Development of an online tool enabling users to perform molecular replacements • Provided multiple datasets, such as synthetically accessible, Fsp 3 -rich drug fragment substitutions obtained through molecular fragmentation. Bioisosteric replacement is an important method for rational drug design. It enables the modification of key pharmacophores or functional groups to achieve desired molecular properties. However, systematic collections and updates in this method are missing at present. Here, we introduce NeBULA (Next-Generation Bioisostere Utility Libraries), which systematically collects, organizes, and checks qualitative bioisosteric replacements from more than 700 authoritative medicinal chemistry references. Based on this large database, we developed a user-friendly online drug optimization tool. It not only provides up-to-date alternatives for bioisosteric replacement from experimental data, but also resolves noticeable issues in current tools. Furthermore, NeBULA provides Fsp 3 -rich bioisosteric replacement SMARTS (SMIRKS) reactions, as well as a library full of drug-like molecules and fragments. Finally, the molecular fragmentation applications inside NeBULA platform offer medicinal chemists numerous fragments for drug fusion and replacement. NeBULA is freely available via the following webpage: http://nebula.alphamol.com.cn:5001 .