Discovery of Targeted Covalent Natural Products against PLK1 by Herb-Based Screening

• DOI: 10.1021/acs.jcim.0c00074
• Publication Date: 2020-05-14T22:29:09Z
• Authors: Hao Liang; Hongbo Liu; Yi Kuang; Limin Chen; Min Ye; Luhua Lai
• Keywords: Natural product; Baicalein; Druggability; Baicalin

Natural products (NPs) are a rich source of drug discovery, and some them act by covalently binding to the targets. Recently, targeted covalent natural product (TCNP) design has gained considerable attention since this approach offers significant benefits in improving biological efficacy decreasing off-target side effects. However, most known TCNPs were discovered chance. Rational approaches for systematic screen much needed. Here, we developed combined computational experimental carry out herb-based screening identify against proper cysteine residues target proteins. The TCNP (HB-TCNP) starts from druggable pocket residue prediction, followed virtual NP database mapping candidate herbs validation. Herbs with time-dependent activity selected, their NPs experimentally tested further NPs. We have successfully applied HB-TCNP anti-PLK1 high efficacy. Cys67 Cys133 ATP PLK1 used search. Five exhibited inhibition extent, among which Scutellaria baicalensis showed potent time dependency. Further studies that main active compounds baicalensis, baicalein baicalin, bind through Cys133. Our study provided an efficient way rationally make better use herb medicines. serves as novel site discovery PLK1.