title: Computational Tools for Allosteric Drug Discovery: Site Identification and Focus Library Design.
abstract: Allostery is an intrinsic phenomenon of biological macromolecules involving regulation and/or signal transduction induced by a ligand binding to an allosteric site distinct from a molecule's active site. Allosteric drugs are currently receiving increased attention in drug discovery because drugs that target allosteric sites can provide important advantages over the corresponding orthosteric drugs including specific subtype selectivity within receptor families. Consequently, targeting allosteric sites, instead of orthosteric sites, can reduce drug-related side effects and toxicity. On the down side, allosteric drug discovery can be more challenging than traditional orthosteric drug discovery due to difficulties associated with determining the locations of allosteric sites and designing drugs based on these sites and the need for the allosteric effects to propagate through the structure, reach the ligand binding site and elicit a conformational change. In this study, we present computational tools ranging from the identification of potential allosteric sites to the design of "allosteric-like" modulator libraries. These tools may be particularly useful for allosteric drug discovery.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine (SJTU-SM), Shanghai, 200025, China.
authors.forename: Wenkang
authors.initials: W
authors.lastname: Huang
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, National Cancer Institute, Frederick, MD, 21702, USA. NussinoR@helix.nih.gov.|Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine (SJTU-SM), Shanghai, 200025, China. jian.zhang@sjtu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D011506:Proteins / Q000737:chemistry; D012984:Software; D014584:User-Computer Interface; D064878:Web Browser
chemical_list: D011506:Proteins
keywords: Allosteric drug design; Allosteric drug discovery; Allosteric modulator; Allosteric site; Allostery