Targeting the BH3 domain mediated protein-protein interaction of Bcl-xL through virtual screening.
Apoptosis, or programmed cell death, forms an important part of the cellular regulation machinery. The Bcl-2 protein family, comprising of proapoptotic and antiapoptotic members, forms an important part of the cells internal apoptotic pathway. Overexpression of the antiapoptotic members of the family in a number of cancer cell lines renders them immune to apoptosis and the ability to survive under conditions of cellular stress. Inhibition of the antiapoptotic members of the Bcl-2 family are, therefore, an interesting target for the development of anticancer therapy. An innovative structure-based virtual screening strategy was developed to identify inhibitors of Bcl-xL, an antiapoptotic member of the Bcl-2 family. Various innovative filters, such as receptor-based pharmacophore, cascade docking approach, cross-docking, and composite scoring with docking pose based descriptors were designed through exhaustive validation studies and implemented in the screening funnel. The 1.8 million 'big-n-greasy' subset from ZINC was screened using the protocol, and 45 compounds were finally selected for biological evaluation against Bcl-xL. The evaluation led to the identification of one low-micromolar and two weaker inhibitors belonging to novel scaffolds. Further evaluation of structure-activity relationships around these scaffolds could help in the development of anticancer leads against Bcl-xL.
Mukherjee
Prasenjit
P
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Desai
Prashant
P
Zhou
Yu-Dong
YD
Avery
Mitchell
M
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D008024:Ligands; D051020:bcl-X Protein