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Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

ABSTRACT: Glutamate carboxypeptidase II (GCPII) is a metalloprotease implicated in neurological diseases and prostate oncology. While several classes of potent GCPII-specific inhibitors exist, the development of novel active scaffolds with different pharmacological profiles remains a challenge. Virtual screening followed by in vitro testing is an effective means for the discovery of novel active compounds. Structure- and ligand-based pharmacophore models were created based on a dataset of known GCPII-selective ligands. These models were used in a virtual screening of the SPECS compound library (∼209.000 compounds). Fifty top-scoring virtual hits were further experimentally tested for their ability to inhibit GCPII enzymatic activity in vitro. Six hits were found to have moderate to high inhibitory potency with the best virtual hit, a modified xanthene, inhibiting GCPII with an IC₅₀ value of 353 ± 24 nM. The identification of this novel inhibitory scaffold illustrates the applicability of pharmacophore-based modeling for the discovery of GCPII-specific inhibitors.

SUBMITTER: Temml V

PROVIDER: S-EPMC9976286 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

Temml Veronika V Kollár Jakub J Schönleitner Theresa T Höll Anna A Schuster Daniela D Kutil Zsófia Z

Journal of chemical information and modeling 20230217 4

Glutamate carboxypeptidase II (GCPII) is a metalloprotease implicated in neurological diseases and prostate oncology. While several classes of potent GCPII-specific inhibitors exist, the development of novel active scaffolds with different pharmacological profiles remains a challenge. Virtual screening followed by in vitro testing is an effective means for the discovery of novel active compounds. Structure- and ligand-based pharmacophore models were created based on a dataset of known GCP ...[more]

PMID: 36799916

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Project description:Inhibitors targeting human glutamate carboxypeptidase II (GCPII) typically consist of a P1' glutamate-derived binding module, which warrants the high affinity and specificity, linked to an effector function that is positioned within the entrance funnel of the enzyme. Here we present a comprehensive structural and computational study aimed at dissecting the importance of the effector function for GCPII binding and affinity. To this end we determined crystal structures of human GCPII in complex with a series of phosphoramidate-based inhibitors harboring effector functions of diverse physicochemical characteristics. Our data show that higher binding affinities of phosphoramidates, compared to matching phosphonates, are linked to the presence of additional hydrogen bonds between Glu424 and Gly518 of the enzyme and the amide group of the phosphoramidate. While the positioning of the P1' glutamate-derived module within the S1' pocket of GCPII is invariant, interaction interfaces between effector functions and residues lining the entrance funnel are highly varied, with the positively charged arginine patch defined by Arg463, Arg534 and Arg536 being the only 'hot-spot' common to several studied complexes. This variability stems in part from the fact that the effector/GCPII interfaces generally encompass isolated areas of nonpolar residues within the entrance funnel and resulting van der Waals contacts lack the directionality typical for hydrogen bonding interactions. The presented data unravel a complexity of binding modes of inhibitors within non-prime site(s) of GCPII and can be exploited for the design of novel GCPII-specific compounds.Pdb id codesAtomic coordinates of the present structures together with the experimental structure factor amplitudes were deposited at the RCSB Protein Data Bank under accession codes 4P44 (complex with JRB-4-81), 4P45 (complex with JRB-4-73), 4P4B (complex with CTT54), 4P4D (complex with MP1C), 4P4E (complex with MP1D), 4P4F (complex with NC-2-40), 4P4I (complex with T33) and 4P4J (complex with T33D).

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Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

Publications

Combination of <i>In Silico</i> and <i>In Vitro</i> Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

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Dataset Information

Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

Publications

Combination of &lt;i&gt;In Silico&lt;/i&gt; and &lt;i&gt;In Vitro&lt;/i&gt; Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.

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OmicsDI is part of the ELIXIR infrastructure

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Combination of <i>In Silico</i> and <i>In Vitro</i> Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors.