@article {Shipra:2012:0929-8665:1302,
title = "Identification of Novel Potent Inhibitors Against Bcl-xL Anti-apoptotic Protein Using Docking Studies",
journal = "Protein and Peptide Letters",
parent_itemid = "infobike://ben/ppl",
publishercode ="ben",
year = "2012",
volume = "19",
number = "12",
publication date ="2012-12-01T00:00:00",
pages = "1302-1317",
itemtype = "ARTICLE",
issn = "0929-8665",
url = "https://www.ingentaconnect.com/content/ben/ppl/2012/00000019/00000012/art00010",
doi = "doi:10.2174/092986612803521602",
keyword = "Bcl-xL protein, Gibbs free energy, tumor genesis, chemical fingerprint, molecular interactions, apoptosis, mitochondrial membrane, molecular docking, anti-cancer therapy, Protein–inhibitor",
author = "Shipra, Gupta and Gauri, Misra and Mohan Chandra, Pant and Prahlad Kishore, Seth",
abstract = "Bcl-xL protein belongs to BCL-2 family which has either pro- or anti-apoptotic activities owing to their importance in the regulation of apoptosis, tumor genesis and cellular responses to anti-cancer therapy. Bcl-xL permeabilize the outer mitochondrial membrane of cells and inhibit
these processes. Proteininhibitor interactions play an important role in regulating the expression of Bcl-xL protein. Here, we report the docking studies that resulted in the identification of new inhibitors distinct from the previously reported inhibitor against this protein. The results
have been validated using Sybyl surflux docking. New potent inhibitors from docking analysis are pentacyclic triterpenoid derivative (2S,4aR,6aR, 6bS,8aS,10R,12R,12aS,12bR,14bR,E)-10,12-dihydroxy-2,4a,14b-trimethyl-9-((((R)-3,4,5-trihydroxy-6-methyl-2H-pyran- 2-yl)oxy)methylene)-1,2,3,4,4a,5,6,6a,6b,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-car-boxylic
acid and 4- alkyl-4-methoxypiperidine derivative 8h (where R= 4-Cl-Ph) that promotes the release of pro-apoptotic proteins from the mitochondria which is a key event in cell death signaling. The compounds form stable complex with protein exhibiting highest binding affinity and Gibbs
free energy. Pentacyclic triterpenoid derivatives compound-201 and piperidine derivative compound-39 are potent inhibitors with Ki value of 172.62nM and 175.24 nM high affinity and inhibitory potency. Salt bridge, pi-pi and hydrogen bonding interactions predominantly contribute towards the
stability of the complexes. These compounds can further be exploited for their potential to enhance apoptosis. We have established the correlation between the experimental Ki value with our computational inhibition constant. The quantitative predictions in this study provide a scope for further
experimental testing giving structural insights into the design and development of novel anticancer drugs.",
}