Synthesis and Cytostatic and Antiviral Profiling of Thieno-Fused 7‑Deazapurine Ribonucleosides

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno­[2′,3′:4,5]­pyrrolo­[2,3-<i>d</i>]­pyrimidines and thieno­[3′,2′:4,5]­pyrrolo­[2,3-<i>d</i>]­pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors

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

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors

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