Computational aided mechanistic understanding of Camellia sinensis bioactive compounds against co‐chaperone p23 as potential anticancer agent

Abstract

Co‐chaperon p23 has been well established as molecular chaperon for the heat shock protein 90 (Hsp90) that further leads to immorality in cancer cells by providing defense against Hsp90 inhibitors, and as stimulating agent for generating overexpressed antiapoptotic proteins, that is, Hsp70 and Hsp27. The natural compounds such as catechins from Camellia sinensis (green tea) are also well known for inhibition activity against various cancer. However, molecular interaction profile and potential lead bioactive compounds against co‐chaperon p23 from green tea are not yet reported. To this context, we study the various secondary metabolites of green tea against co‐chaperon p23 using structure‐based virtual screening from Traditional Chinese Medicine (TCM) database. Following 26 compounds were obtained from TCM database and further studied for extra precision molecular docking that showed binding score between −10.221 and −2.276 kcal/mol with co‐chaperon p23. However, relative docking score to known inhibitors, that is, ailanthone (−4.54 kcal/mol) and gedunin ( 3.60 kcal/mol) along with ADME profile analysis concluded epicatechin (−7.013 kcal/mol) and cis‐theaspirone (−4.495 kcal/mol) as potential lead inhibitors from green tea against co‐chaperone p23. Furthermore, molecular dynamics simulation and molecular mechanics generalized born surface area calculations validated that epicatechin and cis‐theaspirone have significantly occupied the active region of co‐chaperone p23 by hydrogen and hydrophobic interactions with various residues including most substantial amino acids, that is, Thr90, Ala94, and Lys95. Hence, these results supported the fact that green tea contained potential compounds with an ability to inhibit the cancer by disrupting the co‐chaperon p23 activity.

Computational and In Vitro Investigation of (-)-Epicatechin and Proanthocyanidin B2 as Inhibitors of Human Matrix Metalloproteinase 1

“…An interaction profile predicted from on target-ligand calculated using the molecular docking approach can be further validated by molecular dynamics simulation and crystallographic studies [ 82 , 83 , 84 ]. Herein, molecular dynamics (MD) simulation was conducted to find out the stability, conformation, and intermolecular interactions between the ligands and active residues of the MMP-1 protein over a 500-ns interval using the Desmond package.…”

Anticancer properties and mechanism of action of the quassinoid ailanthone

“…He et al, 2016), evoked in a subsequent letter (Peng et al, 2017), provides a solid preclinical background to support the development of this natural product as a new anticancer drug to treat CRPC. Moreover, a new modeling analysis also supported the direct binding of AIT to p23 co‐chaperone (Bharadwaj, Lee, Dwivedi, Yadava, & Kang, 2019).…”

Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations

“…Remarkably, all the poses of selected drugs showed substantial alignment on the SirReal2 inhibitor native conformation in the X-ray crystal structure, demonstrated the occupancy of docked ligands in the selective pocket of Sirt2. Because intermolecular interactions in the docked protein–ligand complex are indicators to understand the complex stability and provide insights into protein inhibition mechanism 54 , 68 , molecular contact profiling was extracted for each docked pose of drugs and re-docked SirReal2 inhibitor with Sirt2. Of note, each drug and SirReal2 inhibitor was noted for intermolecular interactions with the hydrophobic cavity of Sirt2 resides by coupling of Rossmann fold domain and zinc-binding domains (Table 1 )—a region for the deacylation of ε-amino groups of lysines, as found in the X-ray crystal structure of Sirt2-SirReal2 inhibitor 23 .…”