From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Lu      Chen; John      K. Morrow; Hoang      T. Tran; Sharangdhar      S. Phatak; Lei      Du-Cuny; Shuxing      Zhang

doi:10.2174/138161212799436386

Abstract

As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting proteinligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/ optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.

Keywords: Structure-based drug design, protein modeling, focused library design, pharmacophore, flexible docking, high-throughput virtual screening, de novo design, protein-protein interaction, polypharmacology