Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening

Szaszkó, Mária; Hajdú, István; Flachner, Beáta; Dobi, Krisztina; Magyar, Csaba; Simon, István; Lőrincz, Zsolt; Kapui, Zoltán; Pazmany, Tamas; Cseh, Sándor; Dormán, György

doi:10.1007/s11030-016-9717-4

Cited by 17 publications

(11 citation statements)

References 34 publications

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“…While 2D similarity search is useful for hit validation, pharmacophore matching is valuable for extending the activity space with novel chemotypes. Strategy I: Selection of the fragment library via direct 2D similarity search [72]. Collection of potential active fragments toward a biological target starts from the structure of known biologically active compounds (active chemical space), carrying out a 2D similarity search using multi-million compounds libraries (T ≥ 0.65) and then filtering the resulting analogues for physicochemical parameters reflecting the fragment criteria.…”

Section: Discussionmentioning

confidence: 99%

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Szilágyi¹,

Flachner²,

Hajdú³

et al. 2021

Molecules

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Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds’ databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.

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Section: Discussionmentioning

confidence: 99%

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Szilágyi¹,

Flachner²,

Hajdú³

et al. 2021

Molecules

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“…In 2016, Mária Szaszkó, István Hajdú et al obtained 204 QC inhibitory fragments by Fragment‐based drug discovery (FBDD) method based on a known QC inhibitor PBD150 . 15 fragments were chosen by the thermal shift assay with the shifted melting temperature >1 ○ C and 10 out of 15 fragments exhibited the QC inhibitory activities with IC 50 ranging from 12–122 uM.…”

Section: Qc Iinhibitorsmentioning

confidence: 99%

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

et al. 2019

ChemistrySelect

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Alzheimer's disease (AD), a common form of dementia, is a progressive neurodegenerative disease and one of the leading causes of death in the elderly worldwide. The exact underlying pathogenesis of AD remains elusive because of its complexity and involvement of multiple factors. Glutaminyl cyclase (QC) and isoGlutaminyl cyclase (isoQC) belong to the family of the metalloenzymes and catalyze the intramolecular cyclization of N-terminal L-glutamine/glutamate residues of certain proteins into pyroglutamic acid (pGlu). The amyloid protein and the monocyte chemoattractant protein (MCP-1) also known as CCL2 that promotes a cascade of inflammation-related responses are two representative substrates. Moreover, it has been demonstrated that the pyroglutamated Aβ and CCL2 exhibit more severe neurotoxicity than normal Aβ and CCL2. Thus, QC represents one of the attractive targets to develop novel treatments for AD. In this review the recent development of QC inhibitors as anti-AD agents will be summarized.

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“…Therefore, molecular docking approaches are initially performed to preliminary estimate the ligand‐binding pose and affinity 41,42 . Moreover, molecular docking approaches have also been used for screening a large database of compounds, 43,44 which may consist of several millions of compounds such as ZINC, 45 ChEMBL, 46 PubChem, 47 and so forth. Therefore, although their accuracy is not very high, molecular docking approaches play an important role in CADD 48 …”

Section: Introductionmentioning

confidence: 99%

Improving ligand‐ranking of AutoDock Vina by changing the empirical parameters

et al. 2021

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AutoDock Vina (Vina) achieved a very high docking‐success rate, truep^, but give a rather low correlation coefficient, R, for binding affinity with respect to experiments. This low correlation can be an obstacle for ranking of ligand‐binding affinity, which is the main objective of docking simulations. In this context, we evaluated the dependence of Vina R coefficient upon its empirical parameters. R is affected more by changing the gauss2 and rotation than other terms. The docking‐success rate truep^ is sensitive to the alterations of the gauss1, gauss2, repulsion, and hydrogen bond parameters. Based on our benchmarks, the parameter set1 has been suggested to be the most optimal. The testing study over 800 complexes indicated that the modified Vina provided higher correlation with experiment Rset1=0.556±0.025 compared with RDefault=0.493±0.028 obtained by the original Vina and RVina0.25em1.2=0.503±0.029 by Vina version 1.2. Besides, the modified Vina can be also applied more widely, giving R≥0.500 for 32/48 targets, compared with the default package, giving R≥0.500 for 31/48 targets. In addition, validation calculations for 1036 complexes obtained from version 2019 of PDBbind refined structures showed that the set1 of parameters gave higher correlation coefficient (Rnormalset1=0.617±0.017) than the default package (RDefault=0.543±0.020) and Vina version 1.2 (RVina0.25em1.2=0.540±0.020). The version of Vina with set1 of parameters can be downloaded at https://github.com/sontungngo/mvina. The outcomes would enhance the ranking of ligand‐binding affinity using Autodock Vina.

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Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening

Cited by 17 publications

References 34 publications

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

Improving ligand‐ranking of AutoDock Vina by changing the empirical parameters

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