In silico binding affinity studies of phenyl-substituted 1,3-oxazoles with protein molecules

Abstract

The new model approach of interaction between the pharmacophores with bio-molecules, fragment-to-fragment, is presented. It is a new step of the molecular modeling and takes correctly into consideration not only the spatial complementarity of the interacted molecules but also the contribution of the stacking π-π-electron interaction and hydrogen bonds. As an example, the correct analysis of the interaction of the biological active phenyl-substituted 1,3-oxazoles with protein fragments is performed. It was shown that the length and energy of the hydrogen bond uniquely depend on the chemical constitution of both components in the created complex [Pharmacophore(Oxazole)-Biomolecule (H-X)]. The binding energy regularly decreases in the series X → O, S, NH (fragments of the corresponding biomolecules). It should be pointed out that introduction of the conjugated phenyl groups at positions 2 and 5 of oxazoles increase the stability of the possibly generated complex Pharmacophore-Biomolecule [Pharm-BioM] with fragments of the corresponding biomolecules along the core of oxazole by 0.2 and 0.5 kcal/mole. At the same time, modeling of the possibly generated complex [Pharm-BioM] by phenyl substituents at position 2 and 5 of 1,3-oxazole with phenylalanine as a fragment of protein molecules additionally stabilizes complex by 2.5 kcal/mole by π-stacking mechanism. It seems, the observed biological activity of the phenyl substituted 1,3-oxazole is rather connected with the possibility to generate the stable complex due to the formation of additional bonds with other fragments (conjugated phenyl core). The calculations give that such substituents do not cause spatial hindrances with the polypeptide chain.

In silico study of binding affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach

“…with model proton-donor biomolecules show that the Е increases upon annelation of oxazole (and its heteroanalogues) with pyridine cycle. It should be noted that the expansion of the -electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] ISSN 1814-9758. Ukr.…”

“…DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (E) increases from monoheterocycles to their condensed derivatives. The expansion of the -electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with the annelated oxazole by the pyridine cycle.…”

“…Their chemical composition and structural characteristics should influence the stability of such complex. Generally, the interaction of two -electron systems can be estimated by the relative positions of the molecular levels of both molecules as well as the overlapping of their -systems; in MO approximation, the interaction energy E is quantitatively calculated in the approximation of the interaction of MO [18].…”

“…Розширення -електронної системи сполук 1 піридиновим циклом зменшило енергію стабілізації -комплексів та H-B комплексів у порівнянні з розширенням -електронної системи, шляхом введення фенільного радикала у 2 або 5 положення оксазольного кільця, описаних раніше оксазолів [18].…”

“…A biological activity depends on the chemical structures of both a pharmacophore and a target molecules that includes their 3D geometry and electron structure. Recently, we reported [18] the influence of the various conjugated groups (donors, acceptors as well as ambivalent phenyls) in a mono-cyclic oxazole platform on the electron densities of substituted derivatives and on their biological activity using the fragment-to-fragment approach. It was found that the expansion of the -system by introducing the conjugated substituents to oxazole platform influenced their biological activity.…”