Modeling and Intermolecular Binding Analysis of Novel 5-Aryl-1,3,4-Oxadiazole Derivatives with some Macromolecular Cancer Relevant Targets

• Main Authors: رزاقی اصل, نیما, رمضانی, علی, علیخانی, رادین
• Format: Text
• Language: Persian
• Published: 1399
• Subjects: QZ آسیب شناسی; Orca
• Online Access: https://eprints.arums.ac.ir/13674/; https://eprints.arums.ac.ir/13674/1/1-10.pdf; https://eprints.arums.ac.ir/13674/7/89.pdf; https://eprints.arums.ac.ir/13674/8/1-90.pdf; https://eprints.arums.ac.ir/13674/19/DissertationRadinAlikhani.doc; http://lib.arums.ac.ir

Introduction: Cancer, the uncontrollable growth of abnormal cells, is the second leading cause of death following cardiovascular diseases. Further progression of basic sciences and introduction of novel drug design techniques and possibility of predicting ligand-receptor interactions, has led to more attempts to discover, design and develop new anticancer chemicals with the hope of accessing to new drugs to complete the cancer treatment process. 1,3,4-Oxadiazole derivatives due to their unique chemical structure and biological/pharmacological applications, are known as one of the centers of attention in medicinal chemistry. Materials, Instruments and Methods: A few novel previously synthesized 2,5-disubstituted 1,3,4-oxadiazole derivatives (1-17) were subjected to combined systematic docking/quantum mechanical studies against certain previously proven chemotherapeutic receptors. AutoDock4.2 and ORCA quantum chemistry packages were used for modeling studies while LigPlot and Viewer Lite software were applied for obtaining ligand-target binding patterns. Results and Discussions: In the current project, it was tried to explore binding modes/affinities of experimentally validated 1,3,4-oxadiazoles (1-17), to some validated chemotherapeutic targets. Structure binding relationship (SBR) studies showed that chemical structures possessing halogen atoms on 5-substituted phenyl and N-benzyl rings (4 and 17) exhibited superior binding modes/energies with regard to the majority of studied targets, regardless of their cytotoxic activity. A few oxadiazole structures exhibited ΔGbs comparable to or stronger than crystallographic ligands that were previously demonstrated to inhibit intended targets. On the basis of obtained results, a general SAR/SBR for binding of candidate oxadiazoles to binding sites of relevant targets was developed and a few top-ranked 2,5-disubstituted 1,3,4-oxadiazole structures were proposed as potential cytotoxic candidates that were also virtually validated. Moreover; lowest binding energy in the ...