Background: Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed.Results: Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα.Conclusions: Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.

The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to conventional anti-androgenic agents. Resveratrol and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. However, the structural basis for the observed differential activity remains unknown. Here, anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol were studied in LNCaP cells expressing T877A mutant AR and atomistic simulations were employed to establish the structure activity relationship. Interestingly, essential hydrogen bonding contacts and the binding energies of resveratrol analogs with AR ligand binding domain (LBD), emerge as key differentiating factors for varying anti-androgenic action. Among all the analogs, pterostilbene exhibited strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resembled pure anti-androgen, flutamide. Principal component analysis of our simulation studies revealed that androgenic compounds bind more strongly to AR LBD compared to anti-androgenic compounds and provide conformational stabilization of the receptor in essential subspace. The present study provides critical insight into the structure–activity relationship of the anti-androgenic action of resveratrol analogs, which can be translated further to design novel highly potent anti-androgenic stilbenes.

Molecular insight into electronic rearrangements and structural trajectories arising from oxidative damages to DNA backbone is of crucial importance in understanding the effect of ionizing radiation, developing DNA biosensors and designing effective DNA cleaving molecules. Employing a Density Functional Theory based multi-scale Quantum-Mechanical-Molecular-Mechanical (QM/MM) simulation and a suitable partitioning of the Hamiltonian on solvated nucleotide, and single-, and double-stranded DNA, we mimic hydrogen transfer reactions from the backbone by OH radicals and report structural trajectories arising from on-the-fly electronic charge- and spin-density redistribution in these three different structural topologies of DNA. Trajectories reveal that H4 abstraction can disrupt the deoxyribose moiety through the formation of C4=O4 ketone and a -bond with base at C1-N9 in a nucleotide versus only partial ketone formation in single- and double-stranded DNA, where the orientation of the base is topologically restrained. However, H5 abstraction can lead DNA cleavage at 5 end through the formation of C5=O5 ketone and breakage of P-O5 bond. Results demonstrate that structural damages from oxidative reactions are restrained by base stacking and base-pair hydrogen bonding. The methodology can be suitably used to study targeted DNA and RNA damages from radicals and radiomimetic drugs to design DNA cleaving molecules for chemotherapy.