AutoDesigner - Core Design, a De Novo Design Algorithm for Chemical Scaffolds: Application to the Design and Synthesis of Novel Selective Wee1 Inhibitors

The hit identification
stage of a drug discovery program generally
involves the design of novel chemical scaffolds with desired biological
activity against the target(s) of interest. One common approach is
scaffold hopping, which is the manual design of novel scaffolds based
on known chemical matter. One major limitation of this approach is
narrow chemical space exploration, which can lead to difficulties
in maintaining or improving biological activity, selectivity, and
favorable property space. Another limitation is the lack of preliminary
structure–activity relationship (SAR) data around these designs,
which could lead to selecting suboptimal scaffolds to advance lead
optimization. To address these limitations, we propose AutoDesigner
- Core Design (CoreDesign), a de novo scaffold design
algorithm. Our approach is a cloud-integrated, de novo design algorithm for systematically exploring and refining chemical
scaffolds against biological targets of interest. The algorithm designs,
evaluates, and optimizes a vast range, from millions to billions,
of molecules in silico, following defined project parameters encompassing
structural novelty, physicochemical attributes, potency, and selectivity
using active-learning FEP. To validate CoreDesign in a real-world
drug discovery setting, we applied it to the design of novel, potent
Wee1 inhibitors with improved selectivity over PLK1. Starting from
a single known ligand and receptor structure, CoreDesign rapidly explored
over 23 billion molecules to identify 1,342 novel chemical series
with a mean of 4 compounds per scaffold. To rapidly analyze this large
amount of data and prioritize chemical scaffolds for synthesis, we
utilize t-Distributed Stochastic Neighbor Embedding (t-SNE) plots
of in silico properties. The chemical space projections allowed us
to rapidly identify a structurally novel 5–5 fused core meeting
all the hit-identification requirements. Several compounds were synthesized
and assayed from the scaffold, displaying good potency against Wee1
and excellent PLK1 selectivity. Our results suggest that CoreDesign
can significantly speed up the hit-identification process and increase
the probability of success of drug discovery campaigns by allowing
teams to bring forward high-quality chemical scaffolds derisked by
the availability of preliminary SAR.