Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets

De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from‐scratch construction of molecules is not limited to compounds in pre‐existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space. The code was validated using three increasingly difficult classes of calculations: (1) Rebuilding known X‐ray ligands taken from 663 complexes using only their component parts (focused libraries), (2) construction of new ligands in 57 drug target sites using a library derived from ∼13M drug‐like compounds (generic libraries), and (3) application to a challenging protein‐protein interface on the viral drug target HIVgp41. The computational testing confirms that the de novo DOCK routines are robust and working as envisioned, and the compelling results highlight the potential utility for designing new molecules against a wide variety of important protein targets. © 2017 Wiley Periodicals, Inc. De novo design methods aim to create new molecules, from scratch, with steric and electrostatic compatibility for the target system(s). In this work, we describe development, validation, and application of a new de novo design version of the program DOCK that allows assembly of small organic molecules in a binding site using fragment libraries consisting of scaffolds, linkers, and sidechains. The results highlight the potential utility for designing new molecules against a wide variety of important protein targets.