Abstract
Overexpression of murine double minute 2 (MDM2) results in the inactivation of p53 and causes cancer which is a leading cause of death in recent era. In recent decades, much attention has been paid to discover potential inhibitors against MDM2 in order to cure cancer. Outcomes from studies proposes that the MDM2 is a hot target to screen potent antagonists. Thus, this study aims at discovering natural compounds using several computational approaches to inhibit the MDM2 and to eliminate p53-MDM2 interaction, which would result in the reactivation of p53 activity. A library of 500 terpenes was prepared and several virtual screening approaches were employed to find out the best hits which could serve as p53-MDM2 antagonists. On the basis of the designed protocol, three terpenes were selected. In the present study, for the stability and validation of selected three protein-ligand complexes 20 ns molecular dynamics simulations and principal component analyses (PCA) were performed. Results found that the selected terpenes hits (3-trans-p-coumaroyl maslinic acid, Silvestrol and Betulonic acid) are potential inhibitors of p53–MDM2 interaction and could serve as potent antagonists.
Highlights
Cancer is a leading cause of death around the globe in which 56% of total affected population of the world lies in Asia, that is 44% of total global burden with 51% death toll all around the globe [1,2,3].During cancer development normal cells are damaged and turned into cancerous cells through various factors such as cellular signaling stress, DNA damage, disturbance in intercellular and intracellular responses, loss of response to minor nutrients and replacement with carcinogenic material in unhealthy conditions [4]
The binding cleft of murine double minute 2 (MDM2) with p53 has an interaction capability with the 109-amino-acid-long NH2 terminal domain consisting of four α helices and six β sheets where amphipathic helix of transactivation domain comprised eight residues of p53 contact forming intermolecular hydrogen bonds [14]
The current study focused on discovering novel terpenes as antagonists of p53-MDM2 interaction to reactivate p53 running using several virtual screening approaches coupled with molecular dynamics and simulation (MDS)
Summary
Cancer is a leading cause of death around the globe in which 56% of total affected population of the world lies in Asia, that is 44% of total global burden with 51% death toll all around the globe [1,2,3].During cancer development normal cells are damaged and turned into cancerous cells through various factors such as cellular signaling stress, DNA damage, disturbance in intercellular and intracellular responses, loss of response to minor nutrients and replacement with carcinogenic material in unhealthy conditions [4]. Nature created mechanisms to overcome and nullify the effects of such conditions in the body. Several beneficial physio-pathological factors exist in the body for the development and maintenance of cellular communication among the cells [5]. Genetic variation and DNA damage, the cells with genetic lesions are prone to undergo uncontrolled proliferation, which can lead to the development of an unnecessary mass. Under such conditions, elevated levels of p53 play a vital role in the arrest of the cell cycle at
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