Accurate Atomistic Models for Computer-Aided Drug Design – ATMCADD

This project addresses the important problem of the development of accurate atomistic simulation models for computer-aided drug design (CADD). Drug discovery and development are very time and resource consuming processes, which are significantly facilitated by CADD methods. Structure-based CADD methods fundamentally rely on scoring functions to evaluate ligand-target affinities. These simple scoring functions are not accurate enough to reproduce ligand-target interactions in the complex heterogeneous protein-solvent environment. In particular, classical force fields with fixed charges, currently widely used in CADD applications, do not account for induced electronic polarization effects important for ligand:protein binding. Today, there is a clear demand for accurate methods to predict ligand affinities in CADD to speed the discovery of new potential drugs. The primary goal of this project is to develop and implement in CADD a new generation of mechanistic models based on solid physical principles. It is related to the recent advances in next generation atomistic simulation models explicitly treating electronic polarizability. In this project I will extend and implement the polarizable force field based on the classical Drude oscillator model to CADD applications. The main obstacle in using the polarizable force fields in CADD is explained by the treatment of the aqueous solvent, with the current implicit solvent models incompatible with the Drude force field. Moreover, existing CADD methods are challenged by treatment of aqueous solvent, which plays a key role in ligand-target binding. The ATMCADD project will contribute to lifting several technological barriers by designing new solvation models combined with the Drude polarizable force field, and developing cutting-edge methods for solvent treatment in CADD. In particular, in the course of this project I will develop new continuum dielectric medium models for implicit solvation combined with the polarizable force field; develop and implement new models for the vdW dispersive non-polar solvation; and develop new cutting-edge methods for the cavity-formation term, which has been completely neglected in previous studies. The ATMCADD project will be done in collaboration with the main developer of the Drude polarizable force field, making the results of this work highly visible and will create a lasting international collaboration.
The second ultimate goal of this project is to apply these advanced models to the important problem of the development of new potent anticancer and antimicrobial drugs. Together with experimentalists, I will propose new inhibitors of the myeloid cell leukemia-1 (Mcl-1) and Bcl-xL oncoproteins, both implicated in many cancer diseases. Specifically, we will design inhibitors disrupting protein-protein interactions of these oncoproteins with the BH3 domains of their pro-apoptotic counterparts to normalize the function of the later proteins. We will also contribute a new approach to tackle the acute problem of bacterial drug resistance by designing new classes of antibacterial drugs. In particular, we will target a recently discovered mismatch-repairing enzyme present in microbial pathogens, but absent in humans. Therefore, this ambitious project combines important pharmaceutical goals with methodological improvements in CADD empowered by the recent advances in polarizable atomistic models. Beyond the methodological improvements that can be expected from the project, we will provide computer methods and tools that will be made available to the drug-design community through their implementation in popular programs for molecular simulations and CADD. Importantly, due to the foundational character of the new methods that we will develop, they can be applied beyond CADD applications, to a variety fundamental and applied problems, such as accurate pKa prediction of protein groups and ligands, protein folding, and de-novo protein design.