Identification of novel potent inhibitors against Bcl-xL anti-apoptotic protein using docking studies.
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. Protein-inhibitor 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.
Bioinformatics Centre, Biotech Park, Sector-G Jankipuram, Lucknow-226021, Uttar Pradesh, India. shiprabioinfo@gmail.com
Gupta
G
Shipra
Misra
M
Gauri
Pant Mohan
PM
Chandra
Seth Prahlad
SP
Kishore
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013816:Thermodynamics; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D008024:Ligands; D010880:Piperidines; D014315:Triterpenes; D051020:bcl-X Protein