Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design

Abstract

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

“…They consider issues such as the selection or prediction of hydration sites before starting the simulation, the computational methods that can best predict water positions, the ensuing incorporation of explicit water molecules into the docking procedure, and the methods adopted by various software packages [317]. Several works provide information about the development of specific approaches to the identification of the physically ideal positions for explicit water molecules in a simulation and their utilisation in computational software [294,316,[318][319][320][321][322][323][324][325][326].…”

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

“…They consider issues such as the selection or prediction of hydration sites before starting the simulation, the computational methods that can best predict water positions, the ensuing incorporation of explicit water molecules into the docking procedure, and the methods adopted by various softwares [311]. Several works provide information about the development of specific approaches to the identification of the physically ideal positions for explicit water molecules in a simulation, and their utilization in computational softwares [288,310,[312][313][314][315][316][317][318][319][320].…”