THE USE OF PHARMACOPHORE MODELING FOR A PURPOSEFUL SEARCH OF POTENTIAL ANTIHYPERTENSIVE AGENTS OF A NUMBER OF DERIVATIVES OF FIVE-MEMBERED HETEROCYCLES
DOI:
https://doi.org/10.11603/mcch.2410-681X.2019.v.i3.10567Keywords:
pharmacophore modeling, derivatives of five-membered heterocycles – 1,3-thiazole, 1,3,4-thiadiazole, 1,3,4-triazole, antihypertensive activityAbstract
Introduction. Pharmacophore modeling is one of the most effective virtual screening methods. This method allows to determine the set and relative arrangement of specific molecular fragments that are required for the manifestation of a particular biological activity. Increased blood pressure is a major cause of cardiac, vascular, and cerebral complications, including ischemic heart disease, chronic heart failure, and circulatory disorders. Purposeful search for antihypertensive agents using the latest methods, including pharmacophore modeling, among derivatives of five-membered heterocycles is appropriate and relevant. Pharmacophore modeling is one of the most effective virtual screening methods. This method allows to determine the set and relative arrangement of specific molecular fragments that are required for the manifestation of a particular biological activity. Increased blood pressure is a major cause of cardiac, vascular, and cerebral complications, including ischemic heart disease, chronic heart failure, and circulatory disorders. Purposeful search for antihypertensive agents using the latest methods, including pharmacophore modeling, among derivatives of five-membered heterocycles is appropriate and relevant.
The aim of the study – the pharmacophore modeling of a series of five-membered heterocycle derivatives, 1,3-thiazole, 1,3,4-thiadiazole, and 1,3,4-triazole, for the purposeful search for potential antihypertensive agents.
Research Methods. 1,3-thiazole, 1,3,4-thiadiazole and 1,3,4-triazole derivatives with established antihypertensive activity were synthesized as objects of study. Pharmacophore modeling was performed in a specialized program for molecular modeling of chemoinformatics Molecular Operating Environment.
Results and Discussion. In the process of searching for a probable pharmacophore, pharmacophore models have been developed that are characterized by different composition and coordinates of pharmacophore centers, as well as classification accuracy. For the detection and screening of antihypertensive effects, four-component pharmacophore models were selected with a classification accuracy of 0.52–0.61 and an overlap of active compounds of 1.76–2.78. Pharmacophore model with the highest accuracy and degree of overlap structurally consists of an aromatic ring, two hydrophobic regions and a projection of a hydrogen bond acceptor with a characteristic mutual spatial arrangement and through the aromatic interaction mechanism. The structures of the virtual base molecule structures were harmonized with the pharmacophore model.
Conclusions. Conducted pharmacophore modeling of a number of derivatives of five-membered heterocycles – 1,3-thiazole, 1,3,4-thiadiazole and 1,3,4-triazole with established antihypertensive activity made it possible to distinguish a possible pharmacophore consisting of an aromatic ring, two Hydrophobic Areas and Projections of the Hydrogen Bond Acceptor. The accuracy of the classification of active and inactive compounds in this model is 0.61. The resulting pharmacophore model can be used for virtual screening and targeted search for new antihypertensive agents.
Key words: pharmacophore modeling, derivatives of five-membered heterocycles – 1,3-thiazole, 1,3,4-thiadiazole, 1,3,4-triazole, antihypertensive activity.
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