DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

Abstract

Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by “traditional” drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket “observed” from within the protein to the topography “observed” when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human anti-apoptotic protein Mcl-1, and found that 4 of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 µM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions.

The Ser/Thr Protein Kinase Protein-Protein Interaction Map of M. tuberculosis*

“…S2). We note that this methodology also identifies those interactions that are particularly strong (K D value of less than 10 Ϫ7 M) (29). In this way, we found that many of the interactions between the proteins and STPKs were indeed strong, including PknB -EchA7, PknD -FtsX, PknG -PhoH2, and PknH -AccD6.…”

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

“…DARC (Docking Approach using Ray-Casting) [61] is specifically designed to handle the shallow, flat pockets, which is typically observed in PPI sites. DARC works by comparing the topology of a protein surface pocket to the topology of a bound ligand at the binding site.…”

“…Although there are some examples where CADD has been applied to SMPPII discovery [21–23], PPIs remain difficult targets since PPIs and their binding ligands have different characteristics from traditional targets. [24, 25]. To understand the current status of CADD methods for PPI targets, here we review computational tools for discovering SMPPIIs, which try to overcome the hurdles that arise from the different nature of PPIs and compounds that interact with PPIs.…”

Macromolecular Modeling and Design in Rosetta: New Methods and Frameworks

“…Alternatively, these pockets can also be used for Rosetta's Docking Approach using Ray Casting (DARC 31 ) method. DARC uses ray-casting to rapidly position a ligand in the protein surface pocket 31 ; by iterating over many candidates, DARC provides a means for very rapid virtual screening. DARC has also been adapted for GPUs 32 , and the newer implementation 33 includes features that provide improved performance in virtual screening benchmarks.…”