From laptop to benchtop to bedside: structure-based drug design on protein targets.
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.
University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX 77054, USA.
Lu
L
Chen
John K
JK
Morrow
Hoang T
HT
Tran
Sharangdhar S
SS
Phatak
Lei
L
Du-Cuny
Shuxing
S
Zhang
D017076:Computer-Aided Design; D016503:Drug Delivery Systems; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011506:Proteins