【摘 要】
：
We herein describe AncPhore,a versatile tool for drug discovery,which is characterized by pharmacophore feature analysis and anchor pharmacophore(i.e.,most important pharmacophore fea-tures)steered molecular fitting and virtual screening.Comparative analy
【机 构】
：
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Prov
论文部分内容阅读
We herein describe AncPhore,a versatile tool for drug discovery,which is characterized by pharmacophore feature analysis and anchor pharmacophore(i.e.,most important pharmacophore fea-tures)steered molecular fitting and virtual screening.Comparative analyses of numerous protein-ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically impor-tant,commonly associated with protein conservative characteristics,and have significant contributions to the binding affinity.Performance evaluation of AncPhore showed that it had substantially improved pre-diction ability on different types of target proteins including metalloenzymes by considering the specific contributions and diversity of anchor pharmacophore features.To demonstrate the practicability of An-cPhore,we screened commercially available chemical compounds and discovered a set of structurally diverse inhibitors for clinically relevant metallo-β-lactamases(MBLs);of them,4 and 6 manifested potent inhibitory activity to VIM-2,NDM-1 and IMP-1 MBLs.Crystallographic analyses of VIM-2:4 complex revealed the precise inhibition mode of 4 with VIM-2,highly consistent with the defined anchor pharmacophore features.Besides,we also identified new hit compounds by using AncPhore for indolea-mine/tryptophan 2,3-dioxygenases(IDO/TDO),another class of clinically relevant metalloenzymes.This work reveals anchor pharmacophore as a valuable concept for target-centered drug discovery and illus-trates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.
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