Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease

Abstract

Synthesis of serine derivatives having the essential functional groups for the inhibitor of SARS 3CL protease and evaluation of their inhibitory activities using SARS 3CL R188I mutant protease are described. The lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and Bai's cinnamoly inhibitor, and additionally performed with simulation on GOLD softwear. Structure activity relationship studies of the candidate compounds were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant protease. These inhibitors showed protease selectivity and no cytotoxicity.

Keywords: Cathepsin B; Cytotoxicity; Docking simulation; SARS 3CL protease; SARS CoV; Serine derivative.

Graphical abstract

Figure 1

Ac-Thr-Val-Cha-His-H (1) and concept for serine derivative.

Scheme 1

Virtual screening of the serine derivatives for SARS-CoV 3CL protease (PDB code 3AW1) on GOLD softwear.

Scheme 2

Synthetic outline for the preparation of serine derivatives (6a–o and 7b–o).

Figure 2

Docking simulation of selected inhibitors bound to SARS 3CL protease (PDB code 3AW1) using GOLD from CCDC. Molecular graphic image shown using PyMOL from Schrödinger; oxygen (red) and nitrogen (blue) of inhibitors; Cys145 (red) of SARS 3CL protease. (A) Surface mode with 7k, (B) with ent-7k, (C) with ent-3, (D) model of interaction with ent-3.

Figure 3

Optimized inhibitors ent-3 (SK23) and ent-7k (SK69).