SENSAAS-Bioisostere: A computational method for 3D shape-guided bioisosteric replacements and scaffold-hopping

We introduce SENSAAS-Bioisostere, a computational method for identifying bioisosteric replacements or scaffold-hopping. Our process utilizes the matching and sub-matching properties of the method SENSAAS to compare fragments. SENSAAS has been initially developed to align and calculate the similarity between the colored shapes of two molecules. The latest feature, SENSAAS-Bioisostere, specifically identifies fragments that are similar in shape and pharmacophore to a query fragment. It then builds and aligns new molecules on the query molecule. In SENSAAS-Bioisostere, a fragment is represented by a colored 3D point cloud with openings, which characterizes its shape, pharmacophoric features, but also the position of its substituents, all in a single representation. Alignments are achieved through 3D point set registration, a process widely used in computer graphics to align multiple point clouds, by minimizing the distances between pairs of points. SENSAAS-Bioisostere currently uses two data sets: one containing over 9500 fragments extracted from approved drugs, and another containing over 27,000 fragments extracted from co-crystallized molecules. A retrospective analysis of successful scaffold-hoppings confirmed the effectiveness of our approach in the search of new molecules.