Unlocking Scalable Ligand Residence Time Predictions with Koffee Unbinding Kinetics Simulations

Abstract

A great number of drug discovery programs fail due to poor in vivo efficacy and ADMET liabilities. On- and off-target ligand residence times can act as important drivers of these problems. While modern experimental techniques have made measuring compound kinetics data more routine, there is a lack of accurate, high-throughput simulation techniques to guide compound prioritization by residence time. In this work, we introduce Koffee Unbinding Kinetics as a solution to the hitherto unanswered problem of scalable ligand-protein residence time prediction. By bypassing conventional approaches based on molecular dynamics simulations, Koffee Unbinding Kinetics performs physics-based residence time screening at the atomistic level in {approx} 1 GPU minute per complex using inexpensive hardware, a speed-up of at least 3 - 5 orders of magnitude compared to current state-of-the-art simulation approaches. Koffee Unbinding Kinetics can enhance compound selection to mitigate costly future program failures by adding fast, predictive residence time simulations to early-stage computational drug discovery pipelines. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/686759v3_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@120d5dcorg.highwire.dtl.DTLVardef@b86b67org.highwire.dtl.DTLVardef@193554forg.highwire.dtl.DTLVardef@1c5c6c1_HPS_FORMAT_FIGEXP M_FIG C_FIG