Expanding the Palette of Molecular Fragments for Small Molecule De Novo Design Through Isosteric Swapping

Outcomes from fragment-based assembly of small organic molecules are highly dependent on the number and type of fragments available for growth. Here, we present a new chemical searching strategy for the DOCK6 de novo design (DOCK_DN) engine which logically expands the palette of available fragments compared to the current method. Termed DOCK_SWAP, the new routine employs principles of isosteric swapping and a customized library infrastructure (iso-libraries) in which topologically related sidechains, linkers, and scaffolds have been pre-aligned and rank ordered relative to a parent fragment (iso-tables). The primary objectives of the current work are: (I) introduce the DOCK_SWAP infrastructure and algorithms, (II) characterize iso-library expansion outcomes and impact of different alignment and ranking protocols, (III) assess search performance, molecular scores, heterogeneity, and growth path coverage and (IV) evaluate lead refinement. Depending on the protocol, the new iso-libraries are roughly an order of magnitude larger (N = 2197 to 2708) than the existing library (N = 382). Large-scale simulations (N = 3420) across 57 protein–ligand systems, using three different iso-libraries each, confirm that the DOCK_SWAP code base and infrastructure is robust. Although the use of larger DOCK_SWAP iso-libraries come at an increased cost in terms of simulation time, the results highlight the many advantages over the existing DOCK_DN method for design of drug-like ligands with improved complementarity to the sites being targeted.