Structure-based methods that employ principles of de novo design can be used to construct small organic molecules from scratch using pre-existing fragment libraries to sample chemical space and are an important class of computational algorithms for drug-lead discovery. Here, we present a powerful new design method for DOCK6 that employs a Descriptor-Driven De Novo strategy (termed D3N) in which user-defined cheminformatics descriptors (and their target ranges) are calculated at each layer of growth using the open-source toolkit RDKit. The objective is to tailor ligand growth toward desirable regions of chemical space. The approach was extensively validated through: (1) comparison of cheminformatics descriptors computed using the new DOCK6/RDKit interface versus the standard Python/RDKit installation, (2) examination of descriptor distributions generated using D3N growth under different conditions (target ranges and environments), and (3) construction of ligands with very tight (pinpoint) descriptor ranges using clinically relevant compounds as a reference. Our testing confirms that the new DOCK6/RDKit integration is robust, showcases how the new D3N routines can be used to direct sampling around user-defined chemical spaces, and highlights the utility of on-the-fly descriptor calculations for ligand design to important drug targets.