Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors

Vuorinen, Anna; Engeli, Roger T.; Meyer, Arne; Bachmann, Fabio; Griesser, Ulrich J.; Schuster, Daniela; Odermatt, Alex

doi:10.1021/jm5004914

Cited by 63 publications

(44 citation statements)

References 67 publications

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“…However, there are no defined standards for precision (hit rate) and recall (yield) values of pharmacophore based virtual screening, multiple studies have been done to evaluate designed pharmacophores 51–53,57–58. For example, a study on ligand‐based pharmacophore models for discovery of 17β‐Hydroxysteroid Dehydroxygenase 2 inhibitors57 reported hit rate of 24 to 50 % and yield of 40 to 50 %; and another screening by receptor based pharmacophore models designed for HIV‐1 protease inhibitors58 also reported their hit rates (10 to 36 %) and yield values (0.7 to 4.5 %). The hit rates for our pharmacophore models can be summarized as hit rates of 89 to 93 % and yield values of 19 to 20 %.…”

Section: Resultsmentioning

confidence: 99%

An Ab Initio Method for Designing Multi‐Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases

Kaalia¹,

Kumar²,

Srinivasan³

et al. 2015

Molecular Informatics

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For past few decades, key objectives of rational drug discovery have been the designing of specific and selective ligands for target proteins. Infectious diseases like malaria are continuously becoming resistant to traditional medicines, which inculcates need for new approaches to design inhibitors for antimalarial targets. A novel method for ab initio designing of multi target specific pharmacophores using the interaction field maps of active sites of multiple proteins has been developed to design 'specificity' pharmacophores for aspartic proteases. The molecular interaction field grid maps of active sites of aspartic proteases (plasmepsin II & IV from Plasmodium falciparum, plasmepsin from Plasmodium vivax, pepsin & cathepsin D from human) are calculated and common pharmacophoric features for favourable binding spots in active sites are extracted in the form of cliques of graphs using inductive logic programming (ILP). The two pharmacophore ensembles are constructed from largest common cliques by imposing size of receptor active site (L) and domain-specific receptor-ligand information (S). The overlap of chemical space between two ensembles and the results of virtual screening of inhibitor database with known activities show that this method can design efficient pharmacophores with no prior ligand information.

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Section: Resultsmentioning

confidence: 99%

An Ab Initio Method for Designing Multi‐Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases

Kaalia¹,

Kumar²,

Srinivasan³

et al. 2015

Molecular Informatics

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“…This Pharmacophore model was used as 3D query for searching out the matching pharmacophore Hits from diverse databases [DrugBank, MDPI, ZINC, Maybridge HitFinder]. 29,30,32,44,45 The model was represented in Figure 2.…”

Section: The Generation Of the Ligand-based Pharmacophore Modelmentioning

confidence: 99%

A Combination of Pharmacophore Modeling, Molecular Docking and Virtual Screening Study Reveals 3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)- 4H-Chromen-4-One as a Potential Anti-Cancer Agent of COT Kinase

Hussain¹,

Verma²

2018

IJPER

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Background: COT (Tpl2/MAP3K8) is a Serine/ Threonine protein kinase which plays a crucial role in the production of TNF-alpha through the phosphorylation of MEK, ERK pathway and the production of other pro-inflammatory cytokines. Its inhibition has been shown as important to reduce inflammatory diseases and cancer. Material and Methods: Combined Ligand-based and Structure-based pharmacophore model was developed for finding out the potential anticancer agents. These combined pharmacophore model was used as 3D-query for searching the matching pharmacophore features against chemical structure databases such as DrugBank, MDPI, ZINC, Maybridge HitFinder. Docking was performed using Schrodinger software as well as selected Hits were filtered by ADMET properties. Results: Among all the selected Hits Compound 3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4H-chromen-4-one was found to be more potent according to the docking score. Conclusion: A step by step computational pipeline was used to find out the potential anticancer agents. This study suggests that these Hits could be used as anticancer agents against death leading diseases.

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“…[11][12][13][14] Recently, a combined screening strategy of pharmacophore mapping and molecular docking show synergetic effect in virtual screening. 15,16 As such, the integrally globally and partially essential pharmacophoric features for both of ligand and receptor can be simultaneously characterized, thereby showing more preferable performance (e.g.…”

Section: -10mentioning

confidence: 99%

Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

et al. 2017

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An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to in vitro biological tests, and three compounds (A5, A6 and A9) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (B2 and B4). Selectivity profiles of JAK subtype and in vitro anti-cancer activity of the promising compounds were studied, revealing the promising compound B2 was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds A5 and B2 were explored to provide a deeper insight for further structural optimization.

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Ligand-Based Pharmacophore Modeling and Virtual Screening for the Discovery of Novel 17β-Hydroxysteroid Dehydrogenase 2 Inhibitors

Cited by 63 publications

References 67 publications

An Ab Initio Method for Designing Multi‐Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases

An Ab Initio Method for Designing Multi‐Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases

A Combination of Pharmacophore Modeling, Molecular Docking and Virtual Screening Study Reveals 3,5,7-Trihydroxy-2-(3,4,5-trihydroxyphenyl)- 4H-Chromen-4-One as a Potential Anti-Cancer Agent of COT Kinase

Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

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