Modular synthon-based approach - V-SYNTHES was published in Nature 601, 452–459 (2022). It first identifies the best scaffold–synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial method enables rapid detection of the best-scoring compounds in the ultra-large chemical space while performing molecular docking of only a small fraction (<0.1%) of the compounds.
The V-SYNTHES approach will be performed in a few stages:
- We generate a library of fragment-like compounds representing all possible scaffold–synthon combinations for all reactions in the whole Enamine REAL Space (31 Billion molecules), which is referred to as a minimal enumeration Library (MEL).
- The MEL compounds are docked onto the target receptor using energy-based docking of the flexible ligand. About 30 thousand of the top-scoring compounds will be used to apply the proprietary technology CapSelect. The technology will allow us to identify the preferable fragments for future growth into final molecules. The last step would be to filter the fragments for diversity using different criteria (i.e. a single reaction cannot contribute more than 20% of the selection).
- The iterative enumeration of the selected fragments from stage 2.
- The docking screen on the final enumerated subset of the library.
- For the three-component reactions, steps 2 and 3 should be repeated.
The hit selection will be performed in 2 stages:
1. Preliminary selection by applying the classical filters like clogP < 6, LogS > -5, MW < 550, No PAINS, “bad” groups, Tox filters, etc.
2. Post-processing and hit picking by selecting compounds by novelty, diversity, and specific interactions based on known binders. At this stage, Machine learning can be applied.