IN SILICO DOCKING STUDIES OF CORDYCEPIN/PENTOSTATIN IN ADA1

Cordycepin, 3’-deoxyadenosine, is an analog of the nucleoside adenosine extracted from Cordyceps sinensis (C.sinensis). Formed from the combination of Ophiocordyceps sinensis fungi and ghost moth caterpillars, C.sinensis are prized in Eastern medicine for their numerous medical applications and usage in cancer therapy. When taken internally, cordycepin is rendered inactive by adenosine deaminase 1 (ADA1), an enzyme that degrades nucleoside analogs. To prevent cordycepin’s degradation by ADA1, pentostatin (an ADA inhibitor) is co-administered with the drug. As a chemotherapeutic drug, pentostatin has exhibited poor target selectivity and a myriad of side effects in clinical trials.

In this study, alternate co-drugs (cordycepin, pentostatin, and naringin analogs) to replace pentostatin are explored and ranked using the Molecular Operating Environment (MOE) program using the scoring functions ASE, Alpha HB, Affinity d, London dG, and GBVI/WSA. If an in silico library of cordycepin, pentostatin, and naringin analogs are docked into human ADA1, then the highest scoring analogs are potential replacements for pentostatin in the cordycepin/pentostatin combination.w

From a library of 34 structures: analogs D30, D9, D33, D27, and C34 were evaluated through the MOE program to have the most proficient docking scores. Although the entire nucleoside series docked into ADA1 successfully, the naringin series yielded inconsistent data. Future studies include the incorporation of other template analogs (ie. theophylline), the docking of a larger nucleoside library, and optimizing the analogs for laboratory synthesis. If successful, the synthesized compounds can be developed into co-drugs to replace pentostatin and improve the toxicological profile of the cordycepin/pentostatin combination.