AncPhore: A versatile tool for anchor pharmacophore steered drug discovery with applications in discovery of new inhibitors targeting metallo- β-lactamases and indoleamine/tryptophan 2,3-dioxygenases

Abstract

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 features) steered molecular fitting and virtual screening. Comparative analyses of numerous protein-ligand complexes using AncPhore revealed that anchor pharmacophore features are biologically important, commonly associated with protein conservative characteristics, and have significant contributions to the binding affinity. Performance evaluation of AncPhore showed that it had substantially improved prediction 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 AncPhore, 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 indoleamine/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 illustrates the potential of AncPhore to efficiently identify new inhibitors for different types of protein targets.

Keywords: AMPC, asian mouse phenotyping consortium; AP, anchor pharmacophore; AR, aromatic ring; AUC, area under the curve; Anchor pharmacophore; BACE1, beta-secretase 1; BRD4, bromodomain-containing protein 4; CA, carbonic anhydrase; CA2, carbonic anhydrase 2; CDK2, cyclin-dependent kinase 2; CTS, cathepsins; CV, covalent bonding; CatK, cathepsin K; EF, enrichment factor; EX, exclusion volume; GA, genetic algorithm; HA, hydrogen-bond acceptor; HD, hydrogen-bond donor; HIV-P, human immunodeficiency virus protease; HIV1-P, human immunodeficiency virus type 1 protease; HY, hydrophobic; IDO1, indoleamine 2,3-dioxygenase 1; IMP, imipenemase; Indoleamine 2,3-dioxygenase; LE, ligand efficiency; MAPK14, mitogen-activated protein kinase 14; MB, metal coordination; MBL, metallo-β-lactamase; MIC, minimum inhibitory concentration; MMP, matrix metalloproteinase; MMP13, matrix metallopeptidase 13; Metallo-β-lactamase; Metalloenzyme; NDM, new delhi MBL; NE, negatively charged center; NP, without anchor pharmacophore features; PO, positively charged center; RMSD, root mean square deviation; ROC curve, receiver operating characteristic curve; ROCK1, rho-associated protein kinase 1; RT, reverse transcriptase; RTK, receptor tyrosine kinase; SBL, serine beta lactamase; SSEL, secondary structure element length; STK, serine threonine kinase; TDO, tryptophan 2,3-dioxygenase; TDSS, torsion-driving systematic search; TNKS2, tankyrase 2; Tryptophan 2,3-dioxygenase; VEGFR2, vascular endothelial growth factor receptor 2; VIM, verona integron-encoded MBL; Virtual screening.