Potential Deoxycytidine Kinase Inhibitory Activity of Amaryllidaceae Alkaloids: An In Silico Approach

摘要

Background: Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of a couple of alkaloidal secondary metabolites with endued cytotoxic activity, such as pancratistatin ( 1 ), 7-deoxypancratistatin ( 2 ), narciclasine ( 3 ), 7-deoxynarciclasine ( 4 ), trans -dihydronarciclasine ( 5 ), and 7-deoxy- trans -dihydronarciclasine ( 6 ). Nevertheless, preclinical evaluation of these alkaloids has been put on hold because of the limited quantity of materials available from isolation. Aim: To explore the underlying cytotoxic molecular mechanisms of the Amaryllidaceae alkaloids ( 1–6 ) and to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles using chemoinformatic tools. Materials And Methods: AutoDock 4.0 software along with different in silico chemoinformatic tools, namely PharmMapper, Molinspiration, MetaPrint2D, and admetSAR servers, were used to assess the drugability of the Amaryllidaceae alkaloids ( 1–6 ). Results: Deoxycytidine kinase (dCK) (PDB: 1P60) was predicted as a potential target with fitting score of 5.574. In silico molecular docking of ( 1–6 ) into dCK revealed good interactions, where interesting hydrogen bonds were observed with the amino acid residues—Gly-28 and Ser-35—located in the highly conserved P-loop motif. This motif plays a special role in dCK function. Contrary to ( 1 ), in silico pharmacokinetic results have shown good absorption and permeation and thus good oral bioavailability for ( 2–6 ). Conclusion: The in silico docking data have proposed that the reported cytotoxic activity of the Amaryllidaceae alkaloids ( 1–6 ) could be mediated through dCK inhibition. In addition, the ADMET profile of these alkaloids is promising and thus ( 1–6 ) could be candidates for future drug development.