Search citation statements
Paper Sections
Citation Types
Year Published
Publication Types
Relationship
Authors
Journals
The identification and design of selective compounds is important for the reduction of unwanted side effects as well as for the development of tool compounds for target validation studies. This is, in particular, true for therapeutically important protein families that possess conserved folds and have numerous members such as kinases. To support the design of selective kinase inhibitors, we developed a novel approach that allows identification of specificity determining subpockets between closely related kinases solely based on their three-dimensional structures. To account for the intrinsic flexibility of the proteins, multiple X-ray structures of the target protein of interest as well as of unwanted off-target(s) are taken into account. The binding pockets of these protein structures are calculated and fused to a combined target and off-target pocket, respectively. Subsequently, shape differences between these two combined pockets are identified via fusion rules. The approach provides a user-friendly visualization of target-specific areas in a binding pocket which should be explored when designing selective compounds. Furthermore, the approach can be easily combined with in silico alanine mutation studies to identify selectivity determining residues. The potential impact of the approach is demonstrated in four retrospective experiments on closely related kinases, i.e., p38α vs Erk2, PAK1 vs PAK4, ITK vs AurA, and BRAF vs VEGFR2. Overall, the presented approach does not require any profiling data for training purposes, provides an intuitive visualization of a large number of protein structures at once, and could also be applied to other target classes.
The identification and design of selective compounds is important for the reduction of unwanted side effects as well as for the development of tool compounds for target validation studies. This is, in particular, true for therapeutically important protein families that possess conserved folds and have numerous members such as kinases. To support the design of selective kinase inhibitors, we developed a novel approach that allows identification of specificity determining subpockets between closely related kinases solely based on their three-dimensional structures. To account for the intrinsic flexibility of the proteins, multiple X-ray structures of the target protein of interest as well as of unwanted off-target(s) are taken into account. The binding pockets of these protein structures are calculated and fused to a combined target and off-target pocket, respectively. Subsequently, shape differences between these two combined pockets are identified via fusion rules. The approach provides a user-friendly visualization of target-specific areas in a binding pocket which should be explored when designing selective compounds. Furthermore, the approach can be easily combined with in silico alanine mutation studies to identify selectivity determining residues. The potential impact of the approach is demonstrated in four retrospective experiments on closely related kinases, i.e., p38α vs Erk2, PAK1 vs PAK4, ITK vs AurA, and BRAF vs VEGFR2. Overall, the presented approach does not require any profiling data for training purposes, provides an intuitive visualization of a large number of protein structures at once, and could also be applied to other target classes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.