Abstract
Prostate cancer (PCa) is the second most common malignancy amongst men worldwide. Under PCa maintenance therapy drugs acting as antagonists/partial agonists of hormone receptors against the prostate tissue are used in clinical practices. Prominent drugs being Cyproterone acetate, Flutamide, Bicalutamide, they not only cause acute and long-term toxicity, but also develops drug resistance among patients. Our focus has been on phytochemicals which do not exhibit any cytotoxicity and have significant androgen receptor (AR) inhibition activity. As Protein- Ligand interactions play a key role in structure based drug design, so by using molecular docking, we screened 803 phytochemicals and investigated their binding affinity against AR. The three dimensional (3D) structure of AR was retrieved from Protein Data Bank, and docked with 3D Pubchem structures of 803 phytochemicals using Argus Lab. Molecular docking and drug likeness studies were made using ADMET properties while Lipinski’s rule of five was performed for the phytochemicals to evaluate their anti-prostate cancer activity. The results showed that Isobavachin exhibited best binding affinity of −13.73 kcal/mol with AR followed by Glabranin, Anthocyanin and Eriosemation. Our studies therefore reveal that these four phytochemicals could be promising candidates for further evaluation for PCa prevention or management.
Highlights
Prostate cancer (PCa) has emerged as the most frequently diagnosed malignancy among men in Western countries[1]
Studies have shown flavonoids to arrest cell cycle in a dose and time dependent manner and depending on their structure and cancer type, flavonoids can block cell cycle at either G0/G1 or G2/M stage[18, 19]. One such group of flavonoids, the flavonols have been known to have a structural similarity to testosterone thereby indicating a good possibility of their strong interactions with the androgen receptor (AR) and significant anti-androgenic activity in PCa20
Molecular docking is one of such frequently used methods in structure based drug designing because of its ability to predict with a high level of accuracy, the conformation of small-molecule ligands within the appropriate target binding site
Summary
The first pocket of the AR (PDB ID: 1E3G) has an area of 406.9 and volume of 515.8, second identified pocket has an area of 326.7 and volume of 393.2 and the third active site has an area of 203.6 and volume of 344.2 These identified active sites were used to identify the best ligand binding site. During the initial part of the study we docked various commercially available PCa drugs in the identified binding sites to draw a comparison with the binding energy of the phytochemicals (Fig. 1). Our study revealed that among the commercially available PCa drugs, the best docking energy was exhibited by Dihydrotestosterone (DHT) with binding affinity of −13.92 kcal/mol followed by Bicalutamide (−11.83 kcal/mol) and Abiraterone (−10.32 kcal/mol) (Table 2). Molecular properties of all these 122 phytochemicals were investigated using Molinspiration software to satisfy Lipinski’s rule of five, which is essential for rational drug design and to
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