Identification of unique binding site and molecular docking studies for structurally diverse Bcl-xL inhibitors

Abstract

B-cell lymphoma extra large (Bcl-xL) is a member of the Bcl-2 family of proteins. This family has been implicated in the survival of cancer cells. Bcl-xL is known to be over-expressed in hematopoietic disorders and various types of cancers. The purpose of the present study is to develop an in silico model allowing for the identification of structural features influencing the inhibitory activity of Bcl-xL protein based on a diverse dataset of 104 compounds. Molecular docking studies are carried out to explore the binding of structurally diverse inhibitors to Bcl-xL by AutoDock and GOLD programs. The outcome of this investigation establishes the molecular basis for inhibition of Bcl-xL. Most of the compounds docked into the active site of Bcl-xL (PDB code 1R2D) with good docking scores and binding mode. The docking analysis of the highest active molecules—compound 50 (AutoDock binding affinity −10.8) and compound 100 (GoldScore 53.0)—from both the docking programs showed significant interaction with active site amino acid residues and H-bond interactions with the key amino acid residues. Current study identified a novel binding site of Bcl-xL protein. Forty compounds bound to this new binding site which is different from the formerly characterized hydrophobic pocket. The energy values of these potent compounds are also comparable with those binding to the previously reported binding site. This finding will help the researchers in the design of a better drug for the treatment of cancers.