Abstract
Fragment screening is a powerful tool to identify and characterize binding pockets in proteins. We herein present the results of a proof-of-concept screening campaign of a versatile 96-entry fragment library from our laboratory against the drug target and model protein human carbonic anhydrase II. The screening revealed a novel chemotype for carbonic anhydrase inhibition, as well as less common non-covalent interaction types and unexpected covalent linkages. Lastly, different runs of the PanDDA tool reveal a practical hint for its application.
Highlights
IntroductionFragments have become an indispensable tool for lead generation in early state drug discovery.The small molecular weight and thereby low molecular complexity, combined with a comparably high degree of functionalization, renders them ideal probes for protein pockets [1,2]
Fragments have become an indispensable tool for lead generation in early state drug discovery.The small molecular weight and thereby low molecular complexity, combined with a comparably high degree of functionalization, renders them ideal probes for protein pockets [1,2]
We tested its versatility in screenings against several established proteins, among these the well-established drug target and model protein human carbonic anhydrase II
Summary
Fragments have become an indispensable tool for lead generation in early state drug discovery.The small molecular weight and thereby low molecular complexity, combined with a comparably high degree of functionalization, renders them ideal probes for protein pockets [1,2]. These interactions are generally of high quality, as the low molecular complexity of the fragments enables an optimal orientation within the binding site, and facilitates supreme geometrical complementarity between the interacting functional groups of fragment and target, while the risk of deteriorating repulsive interactions of non-optimally placed moieties is reduced [3,4,5,6] They enable, despite the screening of a considerably smaller number of probe molecules, a more efficient coverage of chemical space than drug-like compounds, which increases the possibility of finding a hit in a lead-finding effort with a well-designed fragment library [4,5,6,7]. We tested its versatility in screenings against several established proteins, among these the well-established drug target and model protein human carbonic anhydrase II (hCAII)
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