AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization

TLDR

AutoGrow4 is a tool for generating novel drug‑like molecules and optimizing existing ligands. The authors present AutoGrow4 as an open‑source, semi‑automated drug discovery program and demonstrate its use on PARP‑1 for de novo design and lead optimization. AutoGrow4 employs a genetic algorithm that evolves ligands on demand, supports multiple docking programs, applies chemical filters, multithreading, and flexible selection methods, and was applied to the PARP‑1 catalytic domain. AutoGrow4 is faster, more stable, and more modular than earlier versions, and it generates drug‑like compounds with superior predicted binding affinities and binding modes compared to FDA‑approved PARP‑1 inhibitors. AutoGrow4 is released under the Apache License 2.0 and can be downloaded from http://durrantlab.com.

Abstract

Abstract We here present AutoGrow4, an open-source program for semi-automated computer-aided drug discovery. AutoGrow4 uses a genetic algorithm to evolve predicted ligands on demand and so is not limited to a virtual library of pre-enumerated compounds. It is a useful tool for generating entirely novel drug-like molecules and for optimizing preexisting ligands. By leveraging recent computational and cheminformatics advancements, AutoGrow4 is faster, more stable, and more modular than previous versions. It implements new docking-program compatibility, chemical filters, multithreading options, and selection methods to support a wide range of user needs. To illustrate both de novo design and lead optimization, we here apply AutoGrow4 to the catalytic domain of poly(ADP-ribose) polymerase 1 (PARP-1), a well characterized DNA-damage-recognition protein. AutoGrow4 produces drug-like compounds with better predicted binding affinities than FDA-approved PARP-1 inhibitors (positive controls). The predicted binding modes of the AutoGrow4 compounds mimic those of the known inhibitors, even when AutoGrow4 is seeded with random small molecules. AutoGrow4 is available under the terms of the Apache License, Version 2.0. A copy can be downloaded free of charge from http://durrantlab.com/autogrow4 .