High-Throughput Structure-Based Drug Design (HT-SBDD) Using Drug Docking, Fragment Molecular Orbital Calculations, and Molecular Dynamic Techniques

Abstract

Structure-based drug design (SBDD) is rapidly evolving to be a fundamental tool for faster and more cost-effective methods of lead drug discovery. SBDD aims to offer a computational replacement to traditional high-throughput screening (HTS) methods of drug discovery. This "virtual screening" technique utilizes the structural data of a target protein in conjunction with large databases of potential drug candidates and then applies a range of different computational techniques to determine which potential candidates are likely to bind with high affinity and efficacy. It is proposed that high-throughput SBDD (HT-SBDD) will significantly enrich the success rate of HTS methods, which currently fluctuates around ~1%. In this chapter, we focus on the theory and utility of high-throughput drug docking, fragment molecular orbital calculations, and molecular dynamics techniques. We also offer a comparative review of the benefits and limitations of traditional methods against more recent SBDD advances. As HT-SBDD is computationally intensive, we will also cover the important role high-performance computing (HPC) clusters play in the future of computational drug discovery.

Keywords: Drug development; FMO; Fragment molecular orbitals; High-performance computing; Ligand docking; Molecular dynamics; Structure-based drug design; Virtual screening.