To probe the binding pathway of a selective compound (D089-0563) to c-MYC Pu24 G-quadruplex using free ligand binding simulations and Markov state model analysis.

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.

Dopamine D Receptor-Selective Compounds Reveal Structure-Activity Relationships that Engender Agonist Efficacy.

The dopamine D receptor (DR) plays important roles in cognition, attention, and decision making. Novel DR-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. To identify new DR-selective ligands, and to understand the molecular determinants of agonist efficacy at DR, we report a series of eighteen novel ligands based on the classical DR agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)- N-( m-tolyl)acetamide).