Multidimensional De Novo Design Reveals 5‐HT_2B Receptor‐Selective Ligands

Abstract

We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.

Drug combination therapy increases successful drug repositioning

“…Recently, Reutlinger and co-workers developed a quantitative polypharmacology model for 640 human drug targets [29]. Rodrigues et al designed quantitative bioactivity models to achieve structurally novel, selective, potent and ligand-efficient 5-hydroxytryptamine 2B receptor (5-HT2B) modulators with sustained cell-based effects [30]. Gujral et al combined elastic net regulation with mRNA expression profiling of 32 kinase inhibitors to reveal kinases that are important for epithelial and mesenchymal cell migration [31].…”

In silicoExploration of the Conformational Universe of GPCRs

“…Finally, de novo design techniques are used to assemble small organic ligands from scratch that ideally fulfil steric and electrostatic requirements of the binding site . As an example of this approach the molecular ant algorithm (MAntA) was applied successfully for the development of novel selective, nanomolar, and ligand‐efficient 5‐HT 2B receptor ligands …”

Applicability Domains and Consistent Structure Generation

“…Based on this flow of de novo molecular design, we can effectively design drugs and highly functional products. Table 1 shows recent examples of molecules that were designed de novo using the QSAR or QSPR models [6,[9][10][11][12][13][14][15] . One of the important points in de novo molecular design is that estimated activity or property values are reliable only for virtual molecular structures that are similar to those of the training compounds, whereas any virtual molecular structures can be input into the QSAR or QSPR models.…”