Cytokines in terms of QSAR. Review, evaluation and comparative studies

Abstract

Cytokines represent a class of chemical factors that act as mediators in the complex biological response of inflammation, potentially implicated in various diseases. Therefore, selective inhibition or antagonism of cytokines is a target of anti-inflammatory drug design. The QSAR (Quantitative Structure–Activity Relationships) analysis presented here attempts to identify the structural features and physicochemical properties that are significant for cytokine antagonists or inhibitors and in particular of i) interleukin-5 (IL-5), ii) interleukin-6 (IL-6) and iii) of the chemotactic cytokine (chemokine) interleukin-8 (IL-8). Firstly, a historical aspect of the limited published QSARs is discussed and then a 2D-QSAR analysis was carried out for 26 data sets of compounds using the C-QSAR program of Biobyte. In six cases hydrophobicity appeared to be important. Steric factors in the form of overall molar refractivity (CMR), molar refractivity of the substituent (MR), molar volume (MgVol), Taft’s E_s constant and the sterimol parameters B₁ and B₅ have a significant impact on biological activity in most of the derived equations whereas electronic parameters as σ_p, σ_m or Σ_σ appeared in five cases.

Keywords:

• QSAR
• interleukins
• cytokines
• anti-inflammatory agents
• receptor antagonists

Acknowledgements

The authors are grateful to Biobyte Corp. 201 West 4^th St. Suite 204, Claremont CA 91711, USA and Dr Leo for their support and free access to the C-QSAR program. Especially we appreciate Mike Medlin for his invaluable technical help and support. This research has been done by using the above program via the Internet.

Notes

# Parts of this review have been presented as poster presentations in the 15th Hellenic Symposium on Medicinal Chemistry, 25–27 May 2012, Athens and in the 19th EuroQSAR, 26–30 August 2012, Vienna.