3241-75-6Relevant academic research and scientific papers
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors
Kuhn, Bernd,Tichy, Michal,Wang, Lingle,Robinson, Shaughnessy,Martin, Rainer E.,Kuglstatter, Andreas,Benz, J?rg,Giroud, Maude,Schirmeister, Tanja,Abel, Robert,Diederich, Fran?ois,Hert, Jér?me
, p. 2485 - 2497 (2017)
Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of 10 picks compared to 1 out of 10 for the other approaches. From this result and other additional analyses, we conclude that FEP can be a useful approach to guide this type of medicinal chemistry optimization once it has been validated for the system under consideration.
Tandem synthesis of amides and secondary amines from esters with primary amines under solvent-free conditions
Lee, Jeongbin,Muthaiah, Senthilkumar,Hong, Soon Hyeok
, p. 2653 - 2660 (2014/09/17)
An iridium(III)-catalyzed tandem synthesis of amides and amines from esters under solvent-free conditions is described. A commercially available iridium(III) complex, [Cp*IrCl2]2, with sodium acetate showed the best activity for the synthesis of amides and secondary amines. The amide was formed by ester-amide exchange which generates an alcohol in situ which is subsequently transformed to a secondary amine via hydrogen autotransfer. This synthetic protocol with high atom economy generates water as the sole by-product and can afford amides and amines from various esters in a one-pot reaction, expanding the synthetic versatility of ester transformations.
