آنالیز برهمکنش های بین مولکولی در اُکسادیازول های 2و5-استخلافی در مقابل اهداف مرتبط با سرطان

Title

Analysis of intermolecular binding interactions for novel cytotoxic 2,5-disubstituted oxadiazoles versus cancer relevant targets

English Abstract

Introduction and background: Oxadiazole nucleus is a privileged structure in medicinal chemistry. In continuation to our interest in bioactive heterocycles, a few novel synthesized 1,3,4-oxadiazole derivatives were subjected to structure based modeling with the aim of elucidating intermolecular interactions into chemotherapeutic targets. Selected targets were previously demonstrated to be inhibited by 1,3,4-oxadiazoles. Quantitative and qualitative structure binding relationship analysis of docked oxadiazole derivatives proposed binding affinity/mode for cytotoxic oxadiazole molecules within diverse validated targets. Methods: Ligand-flexible docking studies were performed using the molecular docking software, AutoDock 4.2. To elucidate the interactions of selected targets with 1,3,4-oxadiazole molecules (1-17), all the related structures were docked into the active site of validated decuple receptors. Besides, AutoDock driven binding affinities (ΔGb, ki, and LE) were subjected to linear regression analysis with in vitro target inhibitory activities. Results: Structure–binding relationship (SBR) studies confirmed that chemical structures possessing chlorine and bromine atoms on 5-phenyl ring and N-benzyl moieties (4 and 17) exhibited superior binding modes/energies in the majority of studied targets. Amine & pyrrole NH, and N3 of oxadiazole ring were the most frequent atoms participated in H-bond interactions necessary for the enzyme inhibition. Moreover; linear regression analysis demonstrated that telomerase, epidermal growth factor (EGF), and BCL-2 were desirable targets with relatively acceptable affinity toward oxadiazoles on A549 cell line. Discussion and Conclusion: Multi-target oriented study revealed some insights into binding mode of novel cytotoxic oxadiazole derivatives. On the basis of obtained results, a general structure activity relationship (SAR) pattern for candidate 1,3,4-oxadiazoles were represented and a few novel structures were proposed and virtually validated as potential anticancer agents. Since the assessed macromolecular targets were previously proved to be blocked by 1,3,4-oxadiazoles, the results of this study might be useful in further design of more potent cytotoxic 1,3,4-oxadiazole derivatives.

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