DOGS: Reaction-Driven de novo Design of Bioactive Compounds

TLDR

The software DOGS (Design of Genuine Structures) implements a ligand‑based strategy for automated in silico assembly of potentially novel bioactive compounds. We present a computational method for the reaction‑based de novo design of drug‑like molecules. The method evaluates candidate molecules using a graph‑kernel similarity to known bioactive ligands, constructs them deterministically from 25,144 building blocks and 58 reaction rules while ensuring synthesizability, and proposes a synthesis route for each compound, as illustrated in two prospective case studies. The software successfully generated and synthesized ligand candidates for the human histamine H4 receptor and γ‑secretase, demonstrating effective scaffold‑hopping to novel chemotypes with drug‑like properties.

Abstract

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.