PHARMACOPHORE MODELING OF 3,5-DISUBSTITUTED DERIVATIVES OF (4-METHYL/R-PHENYL-3H-THIAZOL-2-YLIDENE)-R1-PHENYL/CYCLOHEXILAMINES WITH CARDIOPROTECTIVE ACTIVITY
DOI:
https://doi.org/10.11603/2312-0967.2019.1.9923Keywords:
pharmacophore modeling, polysubstituted thiazole derivatives, cardioprotective activityAbstract
The aim of the work. Pharmacophore modeling for 3,5-disubstituted derivatives of (4-methyl/R-phenyl-3H-thiazol-2-ylidene)-R’-phenyl/cyclohexilamines with established cardioprotective activity.
Materials and Methods. The 3,5-disubstituted derivatives of (4-methyl/R-phenyl-3H-thiazol-2-ylidene)-R’-phenyl/cyclohexilamines with established cardioprotective activity were objects of the study. The Molecular Operating Environment (MOE) version 2007.09 was used for pharmacophore simulations. The force field MMFF94x was used in the modeling. The geometry optimization of the conformers was carried out by a stochastic search method.
Results and Discussion. The 8 models were developed and characterized by different composition, accuracy of classification and coordinates of pharmacophore centers. The presence of hydrogen bond acceptors and hydrophobic regionsin the active molecules play a key role in all models. The established pharmacophore model contains two pairs of pharmacophore centers located on opposite edges and one hydrophobic region located near the center of the pharmacophor. Each of these pairs is formed from closely spaced (2.85 and 3.79 Å distances respectively) of the hydrophobic pharmacophoric center and the projection of a hydrogen bond donor.
Conclusions. The possible pharmacophore which consists from three hydrophobic regions and two projections of hydrogen bond acceptors was identefied in the pharmacophore modeling for 3,5-disubstituted derivatives of (4-methyl/R-phenyl-3H-thiazol-2-ylidene)-R’-phenyl/cyclohexilamines with investigated in vivo cardioprotective properties The accuracy of the classification of active and inactive compounds by this model is 0.73. The hypothesis about the participation of the acethyl group, the imino group and possibly the distal Nitrogen atom of piperazine moiety in conjunction with the amino acids – hydrogen exchange biotargets was advanced on the basis of the analysis of the compound conformation with the highest cardioprotective activity. The resulting pharmacophore model will be further used for in silico screening molecular databases to identify virtual hits and purposefully search for new cardioprotectors.
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