Molecular docking of anti-inflammatory drug diclofenac with metabolic targets: Potential applications in cancer therapeutics

• Published in: Journal of theoretical biology 2019-03, Vol.465, p.117-125
• Main Authors: Pandey, Shrish Kumar, Yadav, Saveg, Goel, Yugal, Temre, Mithlesh Kumar, Singh, Vinay Kumar, Singh, Sukh Mahendra
• Format: Article
• Language: English
• Subjects: Cancer metabolism; Cancer therapeutics; Diclofenac; Inflammation; Molecular docking
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2019.01.020

•Tumor cells display augmented inflammation & reprogrammed metabolism.•Diclofenac is a potent NSAID which inhibit tumor metabolism.•Molecular docking analysis revealed multiple targets of diclofenac.•Docking targets included molecules regulating tumor metabolism.•Diclofenac possesses potential for anticancer therapeutics. Diclofenac is a potent NSAID of clinical choice, which is widely used for containing inflammation. Moreover, recent experimental evidences overwhelmingly substantiate its antineoplastic potential. However, the precise molecular mechanisms of diclofenac's anticancer activity remain poorly understood. Neoplastic cells display reprogrammed metabolic features, which are manifested and regulated by a complex networking of molecular pathways. However, the effect of diclofenac on tumor cell metabolism are not yet clearly deciphered. Hence, the present investigation was carried out to identify and characterize key diclofenac targets of tumor metabolism, cell survival and chemoresistance. The interactions of diclofenac with such targets was analysed by PatchDock and YASARA (Yet Another Scientific Artificial Reality Application). The docking ability of diclofenac with its targets was based on analysis of dissociation constant (Kd), geometric shape complementarity score (GSC score), approximate interface area (AI area) and binding energy. The findings of this investigation reveal that diclofenac is capable of interacting with all of the selected molecular targets. Prominent interactions were observed with GLUT1, MCT4, LDH A, COX1, COX2, BCRP/ABCG2, HDM2/MDM2 and MRP1 compared to other targets. Interactions were of noncovalent nature involving ionic, hydrophobic interactions, Van der Waals forces and H-bonds, which varied depending on targets. This study for the first time, characterizes the nature of molecular interactions of diclofenac with selected targets involved in cancer cell metabolism, pH homeostasis, chemosensitivity, cell signalling and inflammation. Hence, these findings will be highly beneficial in optimizing the utility of diclofenac in development of novel cancer therapeutics. [Display omitted]