title: Targeting serpins in high-throughput and structure-based drug design.
abstract: Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in mechanisms of health (e.g., enzyme inhibition) and disease (serpinopathies). This intrinsic tendency is modifiable by ligand binding, thus structure-based drug design is an attractive strategy in the serpinopathies. This can be viewed as a labor-intensive approach, and historically, its intellectual attractiveness has been tempered by relatively limited success in development of drugs reaching clinical practice. However, the increasing availability of a range of powerful experimental systems and higher-throughput techniques is causing academic and early-stage industrial pharmaceutical approaches to converge. In this review, we outline the different systems and techniques that are bridging the gap between what have traditionally been considered distinct disciplines. The individual methods are not serpin-specific. Indeed, many have only recently been applied to serpins, and thus investigators in other fields may have greater experience of their use to date. However, by presenting examples from our work and that of other investigators in the serpin field, we highlight how techniques with potential for automation and scaling can be combined to address a range of context-specific challenges in targeting the serpinopathies.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Yi-Pin
authors.initials: YP
authors.lastname: Chang
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahadeva
authors.forename: Anathe O M
authors.initials: AO
authors.lastname: Patschull
authors.forename: Irene
authors.initials: I
authors.lastname: Nobeli
authors.forename: Ugo I
authors.initials: UI
authors.lastname: Ekeowa
authors.forename: Adam R
authors.initials: AR
authors.lastname: McKay
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Thalassinos
authors.forename: James A
authors.initials: JA
authors.lastname: Irving
authors.forename: Imran
authors.initials: I
authors.lastname: Haq
authors.forename: Mun Peak
authors.initials: MP
authors.lastname: Nyon
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Adriana
authors.initials: A
authors.lastname: Ordóñez
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.forename: Bibek
authors.initials: B
authors.lastname: Gooptu
mesh_terms: D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D004055:Differential Thermal Analysis; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013058:Mass Spectrometry / Q000379:methods*; D008956:Models, Chemical; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D054852:Small Molecule Libraries; D000515:alpha 1-Antitrypsin