Computational Infrastructure for Automated Force Field Development and Optimization

Project Abstract Our overarching goal is to provide reliable and efficient tools that can be used in structure based drug discovery (SBDD). One crucial component of SBDD is to predict the structure of a drug molecule that binds to a protein involved in a certain disease. This is usually achieved using

computer tools and the process consists of two steps, namely hit identification and lead optimization. The latter step requires high accuracy and is presently achieved by computing relative binding free energies (RBFE) using alchemical methods and molecular mechanics (MM) forcefields. Unfortunately, due to deficiencies in MM forcefields, predicted drug candidates using

the SBDD process are sometimes unreliable, which is only realized at the later stages of the drug discovery process involving experimental studies or even clinical trials. To address this issue, we will create a novel, flexible and user-friendly computational infrastructure named Automated Force Field Developer and Optimizer (AFFDO) that will allow scientists to quickly generate high-quality

training datasets through high-throughput ab initio calculations and transform them into fast and accurate models which can then be used for RBFE calculations. We will engineer a commercial quality code and deploy it on an existing web-based, user-friendly, drug development platform that is widely popular among the industrial community (OpenEye’s Orion platform).