V-SYNTHES

V-SYNTHES, powered by MolSoft ICM-VLS, is a structure-based virtual screening platform designed to enable efficient and accurate screening of ultra-large chemical libraries — including the 21 billion compound Enamine REAL Space. Developed in collaboration with Prof. Vsevolod Katritch's laboratory at USC and published in Nature, V-SYNTHES is built for drug discovery teams seeking to identify novel lead compounds from giga-sized combinatorial databases without sacrificing docking accuracy.

The platform leverages MolSoft's ICM-Pro technology as its core docking engine, combining advanced cheminformatics, flexible receptor-ligand docking, and hierarchical screening protocols. The approach has been validated in the discovery of new lead compounds for the GPCR target CB2 and the kinase ROCK1, demonstrating its applicability across diverse therapeutic target classes.

Core Technology and Methodology

• Uses MolSoft's ICM-Pro as the primary docking engine for fragment docking, library enumeration, and reaction library preparation
• Employs a Biased Probability Monte Carlo method combined with an optimized force field for accurate docking and scoring
• Applies an empirical scoring function derived from fragment docking results to rapidly evaluate much larger compound libraries
• Top-scoring hits are re-docked and rescored in a final refinement step, ensuring high-quality lead identification
• Hierarchical screening protocol dramatically accelerates docking runs, making it feasible to screen libraries of up to 48 billion compounds

Flexible Receptor Docking and Library Screening

• Incorporates MolSoft's 4D docking methodology, which uses an ensemble of receptor structures to represent binding pocket flexibility
• Enables fast and accurate flexible-receptor ligand docking across giga-sized virtual databases
• Supports screening of major ultra-large libraries including the Enamine REAL Space and the NIH SAVI database
• Integrates GIGA search and RIDE (a shape property-based pharmacophoric search method) as complementary screening tools

Workflow Overview

1. Prepare reaction libraries and enumerate the giga-sized virtual combinatorial database using ICM-Pro
2. Perform fragment-based docking using the Biased Probability Monte Carlo method and optimized force field
3. Derive an empirical score from fragment docking results and apply it to the full expanded library
4. Re-dock and rescore top-ranked hits for final lead selection
5. Utilize ICM scripts available via the Katritch lab GitHub repository, compatible with ICM-Pro and the VLS desktop modeling software

V-SYNTHES is available through MolSoft's ICM-Pro Virtual Ligand Screening desktop modeling software. Additional ICM scripts used in the published workflow are freely available for download from the Katritch lab GitHub site. Organizations interested in applying this approach to their drug discovery programs can contact MolSoft directly for guidance and support.