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D089-0563 is a highly promising anti-cancer compound that selectively binds the transcription-silencing G-quadruplex element (Pu27) at the promoter region of the human c-MYC oncogene; however, its binding mechanism remains elusive. The structure of Pu27 is not available due to its polymorphism, but the G-quadruplex structures of its two shorter derivatives in complex with a ligand (Pu24/Phen-DC3 and Pu22/DC-34) are available and show significant structural variance as well as different ligand binding patterns in the 3′ region. Because D089-0563 shares the same scaffold as DC34 while having a significantly different scaffold from Phen-DC3, we picked Pu24 instead of Pu22 for this study in order to gain additional ligand binding insight. Using free ligand molecular dynamics binding simulations (33 μs), we probed the binding of D089-0563 to Pu24. Our clustering analysis identified three binding modes (top, side, and bottom) and subsequent MMPBSA binding energy analysis identified the top mode as the most thermodynamically stable. Our Markov State Model (MSM) analysis revealed that there are three parallel pathways for D089-0563 to the top mode from unbound state and that the ligand binding follows the conformational selection mechanism. Combining our predicted complex structures with the two experimental structures, it is evident that structural differences in the 3′ region between Pu24 and Pu22 lead to different binding behaviors despite having similar ligands; this also explains the different promoter activity caused by the two G-quadruplex sequences observed in a recent synthetic biology study. Based on interaction insights, 625 D089-0563 derivatives were designed and docked; 59 of these showed slightly improved docking scores. 

Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPAR γ and a partial activation of PPAR α and PPAR β / δ ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPAR α , PPAR β / δ , and PPAR γ , followed by 3  μ s molecular dynamics simulations for each system. Our MM-GBSA binding energy calculation revealed that chiglitazar most favorably bound to hPPAR γ (-144.6 kcal/mol), followed by hPPAR α (-138.0 kcal/mol) and hPPAR β (-135.9 kcal/mol), and the order is consistent with the experimental data. Through the decomposition of the MM-GBSA binding energy by residue and the use of two-dimensional interaction diagrams, key residues involved in the binding of chiglitazar were identified and characterized for each complex system. Additionally, our detailed dynamics analyses support that the conformation and dynamics of helix 12 play a critical role in determining the activities of the different types of ligands (e.g., full agonist vs. partial agonist). Rather than being bent fully in the direction of the agonist versus antagonist conformation, a partial agonist can adopt a more linear conformation and have a lower degree of flexibility. Our finding may aid in further development of this new generation of medication.