Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics.

The optimization of hit compounds into drug candidates is a pivotal phase in drug discovery but often hampered by cumbersome manual synthesis of derivatives. While automated organic molecule synthesis has enhanced efficiency, safety, and cost-effectiveness, achieving fully automated multistep synthesis remains a formidable challenge due to issues such as solvent and reagent incompatibilities and the accumulation of side-products. We herein demonstrate an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics, guided by docking simulations, to identify potent broad-spectrum antiviral leads.

Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson's disease.

A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist.

Novel adenosine A(2A) receptor ligands: a synthetic, functional and computational investigation of selected literature adenosine A(2A) receptor antagonists for extending into extracellular space.

Growing evidence has suggested a role in targeting the adenosine A2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies.