Structural Chemistry

, Volume 30, Issue 6, pp 2311–2326 | Cite as

Diarylthiazole and diarylimidazole selective COX-1 inhibitor analysis through pharmacophore modeling, virtual screening, and DFT-based approaches

  • Luminita Crisan
  • Ana Borota
  • Alina BoraEmail author
  • Liliana PacureanuEmail author
Original Research


The current work is focused on in silico modeling of COX-1 inhibitors with enhanced safety gastric profile. A 5-point pharmacophore model, atom-based 3D quantitative structure-activity relationship (3D-QSAR) and electronic properties were computed for a series of COX-1 inhibitors. The best pharmacophore model AAHRR.10 consisting of two hydrogen bond acceptors, one hydrophobic site, and two rings was developed to derive a predictive, statistically significant 3D-QSAR model at three partial least square factors (R2 = 0.991, SD = 0.059, F = 278.5, Q2 = 0.682, RMSE = 0.325, Pearson’s R = 0.903, Spearman’s rho = 0.872). The AAHRR.10 hypothesis was validated by enrichment studies employing a custom-made validation dataset adopting selective COX-1 inhibitors extracted from ChEMBL and decoys generated via DUD methodology. The global reactivity descriptors, such as HOMO and LUMO energies, the HOMO-LUMO gaps, global hardness, softness, Fukui indices, and electrostatic potential, were carried out using density functional theory (DFT) to confirm the key structural features required to achieve COX-1 selectivity. Well-validated AAHRR.10 hypothesis was further used as 3D query in virtual screening of the DrugBank database to detect novel potential COX-1 inhibitors. Docking algorithm was applied to enhance the pharmacophore prediction and to recommend drugs for repositioning, which can interact selectively with COX-1.


COX-1 Pharmacophore mapping DFT Global reactivity descriptors Drug repurposing 



The authors thank Dr. Ramona Curpăn (“Coriolan Dragulescu” Institute of Chemistry, Romanian Academy), for providing access to Schrödinger software acquired through the PN-II-RU-TE-2014-4-422 projects funded by CNCS-UEFISCDI Romania, to OpenEye, BIOVIA Discovery Studio, and Chemaxon for the free academic licenses.

Funding information

This project was financially supported by Project 1.2 of the “Coriolan Dragulescu” Institute of Chemistry, Romanian Academy.

Compliance with ethical standards

The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material

11224_2019_1414_MOESM1_ESM.pdf (635 kb)
ESM 1 (PDF 634 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.“Coriolan Dragulescu” Institute of Chemistry, Romanian AcademyTimisoaraRomania

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