In silico screening of drug-like molecules for the treatment of cardiovascular diseases on the basis of five-membered privileged heterocycles

Keywords: in silico, five-membered heterocycles, cardiovascular diseases, drug-like molecules


Among various heterocyclic systems, the derivatives of five-membered heterocycles are of special interest. Most of the above mentioned heterocycles are treatred as so-called privileged structures in modern medicinal chemistry. In silico screening among five-membered heterocycles of molecules for the treatment of cardiovascular diseases is actual.

The aim of the work was the search for synthetic drug-like molecules based on functionalized five-membered heterocycles and related heterocyclic systems as an element of the theoretical platform for rational design of compounds acting on the cardiovascular system, and prediction of their possible mechanism of action.

The objects of the study were derivatives of uncondensed and condensed five-membered heterocycles. In the work, in silico approaches were applied using the programs: Hyper-Chem, PASS, AutoDock, PROTOX.

Based on the previous studies, focused sub-libraries of small synthetic drug-like molecules based on functionalized five-membered heterocycles and related heterocyclic systems have been selected. The compounds were divided on 12 groups. The optimization of the compound structures, the drug-like parameters calculation were carried out. The activity prediction, the acute toxicity level and docking studies to probable bio-targets which are related with cardiovascular drug mechanism of action have been carried out. It was shown that thiazole and thiadiazole based compounds possessed the highest calculated affinity levels to selected bio-targets. This is consistent with PASS-based prediction data.

Diverse functionalized derivatives of five-membered heterocycles (thiazole, thiazolidine, thiadiazole, pyrazole, thiophene, triazole)  and related fused heterocycles have been grouped in focused sub-libraries of compounds. it has been established that thiazole and thiadiazole based compounds are promising objects for directed synthesis and further modification as potential cardiovascular agents based on the prediction of biological activity, the calculation of affinity to potent bio-targets, and the prediction of the drug-like features and acute toxicity level. The prognostic values of the parameters of the above mentioned groups of compounds may be used as the element of theoretical platform for the search and de novo design of potential drugs for the treatment of cardiovascular diseases.


1. Morphy R., Rankovic Z. The Physicochemical Challenges of Designing Multiple Ligands // J. med. chem. – 2006. – V. 49, N 16. – Р. 4961–4970.
2. Welsch M. E., Snyder S. A., Stockwell B. R. Privileged scaffolds for library design and drug discovery // Current opinion in chemical biology. – 2010. – V. 14, N 3. – Р. 347–361.
3. Oh S., Park S. B. A design strategy for drug-like polyheterocycles with privileged substructures for discovery of specific small-molecule modulators // Chemical Communications. – 2011. – V. 47, N 48. – Р. 12754–12761.
4. Mendgen T., Steuer C., Klein C. D. Privileged scaffolds or promiscuous binders: a comparative study on rhodanines and related heterocycles in medicinal chemistry // J. med. chem. – 2012. – V. 55, N 2. – Р. 743–753.
5. Klekota J., Roth F. P. Chemical substructures that enrich for biological activity // Bioinformatics. – 2008. –V. 24, N 21. – P. 2518–2525.
6. Srinivas Reddy, Shuxing Zhang. Polypharmacology: drug discovery for the future // Expert Rev. Clin. Pharmac. – 2013. – V. 6, N 1.
7. Koene R. J., Prizment A. E., Blaes A., Konety S. H. Shared Risk Factors in Cardiovascular Disease and Cancer // Circulation. – 2016. – V. 133, N 11. – P. 1104–1114.
8. Nan Wua, Yizhen Xiec, Burton B. Yang. Anti-cancer drugs for cardioprotection // Cell cycle. – 2017. – V. 16, N 2. – P. 155–156.
9. HyperCube, Inc.: Hyperchemsoftware. Hypercube, Inc, 1115 NW 4thStreet, Gainesville, FL 32601 USA.
10. РАSS C&T (Prediction Activity Spectra for Substances: Complex & Training) [Electronic resource] – Access to the resource:
11. AutoDock 4.2 [Electronic resource] – Access to the resource:
12. Protein Data Bank (PDB) [Electronic resource] – Access to the resource:
13. PROTOX [Electronic resource] – Access to the resource:
14. Globally Harmonized System of Classification and Labeling of Chemicals categories – N-Y: United Nation, 2015. – 527 p.
15. Lipinski C. A., Lombardo F., Dominy B. W. at al. Experimental and computational approaches to estimate solubility and permeabilityin drug discovery and development settings // Advanced Drug Delivery Rev. – 2012. – V. 64. – P. 4–17.
16. Filimonov D. A., Lagunin A. A, Gloriozova T. A. at al. Prediction of the biological activity spectra of organic compound using the PASS online web-resource // Chemistry Heterocyclic Compounds. – 2014. – V. 50, N 3. – Р. 444–457.
17. David E. Levy, Chien-kuo Lee What does Stat3 do. // J. Clin. Investigation. – 2002. – V. 109 (9). – P. 1143–1148.
18. Моsula L. М., Zimenkovsky B. S., Ogurtsov V. V. ta in. Protypuchlynna actyvnist ta QSAR-analis pohidnyh rodaninu z benztiazolnym fragmentom u molekulah // Farmats. zh. – 2010. – № 2. – S. 77–83.
19. Kryschyshyn А. P., Drapak І. V., Zimenkovsky B. S. ta in. Іn silico pidhody dlya racionalnoho dysaynu potenciynyh protyracovyh agentiv z grupy chromeno [4',3':4,5]tiopirano[2,3-d]tiazolu // Klin. farmaciya, farmacoterapiya ta medychna standartyzaciya. – 2011. – № 1–2 (10–11). – S. 188–196.
20. Liang Xiao, Karla K. V. Haack, Irving H. Zucker Angiotensin II regulates ACE and ACE2 in neurons through p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 signaling // Amer. J. Cell-Phisiology. – 2013. – V. 304, N 11. – Р. 1073–1079.
21. Anthony C. S., Corradi H. R. AngiotensinConvertingEnzyme N domain glycsoylation mutant (Ndom389) incomplexwith RXP407 // J. Biol. Chem. – 2010. – V. 285. – P. 35685–35693.
22. Casimiro-Garcia A., Filzen G. F., Flynn D. et al. X-ray crystal structure of the nuclear hormone receptor PPAR-gammain a complex with a compound with dual PPAR gamma agonismand Angiotensin II Type I receptor antagonism activity // J. med. chem. – 2011. – V. 54. – P. 4219–4233.
23. Kramer G. J., Mohd A. Human testis angiotensin converting enzyme in complex with K-26 // Med. Chem. Lett. – 2014. – V. 283. – P. 4347–4369 .
24. Krojer T., Kochan G., McDonough M. A. et al. Crystal Structure of Human gamma-butyrobetaine,2-oxoglutarate dioxygenase 1 (BBOX1) // Chem. Biol. – 2010. – V. 17. – P. 1316–1324.
25. Ferraroni M. Crystal structure of human carbonicanhydrase II in complex with the 5-(3-(4-chlorophenylsulfonyl)ureido)pyridine-2-sulfonamide inhibitor-pdb. – 2013.
26. Sippel K. H., Robbins A. H., Domsic J. et al. High-resolution structure of human carbonic anhydrase II complexed with acetazolamide reveals insights into inhibitor drug design // Acta Crystallografica. – 2009. – V. 65. – P. 992–995.
27. Zoë Fisher S., Mayank Aggarwal, Andrey Y. Kovalevsky et al. Neutron Diffraction of Acetazolamide-Bound Human Carbonic Anhydrase II Reveals Atomic Details of Drug Binding // J. Amer. Chem. Society. – 2012. – V. 134, N 36. – P. 14726–14729.
28. Tang L., El-Din T. M., Swanson T. M. et al. Structural basis for inhibition of a voltage-gated Ca(2+) channel by Ca(2+) antagonist drugs // Nature. – 2016. – V. 537. – P. 117–121.
How to Cite
DrapakІ. V. (2019). In silico screening of drug-like molecules for the treatment of cardiovascular diseases on the basis of five-membered privileged heterocycles. Farmatsevtychnyi Zhurnal, (4), 61-72.
Synthesis and analysis of biologically active compounds