Abstract
Although the motions of proteins are fundamental for their function, for pragmatic reasons, the consideration of protein elasticity has traditionally been neglected in drug discovery and design. This review details protein motion, its relevance to biomolecular interactions and how it can be sampled using molecular dynamics simulations. Within this context, two major areas of research in structure-based prediction that can benefit from considering protein flexibility, binding site detection and molecular docking, are discussed. Basic classification metrics and statistical analysis techniques, which can facilitate performance analysis, are also reviewed. With hardware and software advances, molecular dynamics in combination with traditional structure-based prediction methods can potentially reduce the time and costs involved in the hit identification pipeline.
Highlights
Proteins are flexible macromolecular structures that can undergo a wide range of motions considered fundamental for their function
While we focus on virtual screening examples here, the concepts introduced are general and apply to other classification problems that occur in structure-based drug design (SBDD)
Molecular dynamics is increasingly being included in academic high-throughput efforts for pharmaceutically relevant prediction research, and the future is bright
Summary
Proteins are flexible macromolecular structures that can undergo a wide range of motions considered fundamental for their function. Two major types of predictions are discussed including binding site classification, and virtual screening. This review discusses these concepts and how molecular dynamics conformational diversity can enhance the structure-based drug design process.
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