Abstract
We have herein computationally examined binding affinities and specificity of 2-hydroxy-3,5-dinitrobenzamide (HDNB), a small chemical molecular BH3-mimetic identified by means of peptidodynmimetic method, on the BH3-binding grooves of six anti-apoptotic proteins (Bcl-2, Bcl-B, Bcl-W, Bcl-XL, Bfl-1 and Mcl-1) from human beings. The HDNB ligand was found to interact on the BH3-binding grooves of Bcl-2, Bcl-B, Bcl-XL, Bfl-1 and Mcl-1, whereas it did not act as BH3-mimetic to Bcl-W. Moreover, binding affinities of the HDNB towards the anti-apoptotic proteins were significantly different from each other. The differential binding affinities and specificity of the HDNB towards the anti-apoptotic proteins have been chiefly attributed to the differences in the chemical properties of BH3-binding grooves of the proteins. Implications of the study to design efficient de novo antagonists to the anti-apoptotic proteins using the HDNB as seed molecule have been discussed.
Highlights
Apoptosis is tightly regulated by intrinsic pathway activated by Bcl-2 family proteins present in the mitochondrial membrane and anti-apoptotic proteins of the Bcl-2 family are important cancer biomarkers as they are over expressed in all types of cancers (Kelly and Strasser, 2011)
We have studied binding affinities of the HDNB with each anti-apoptotic protein using molecular docking methods and stringently scrutinized mode of interactions of the lead with the proteins
The energy minimized structures were subjected to molecular dynamics (MD) simulations in near physiological conditions for 5 ns at 310 K by Gromacs 4.5.1
Summary
Apoptosis is tightly regulated by intrinsic pathway activated by Bcl-2 family proteins present in the mitochondrial membrane and anti-apoptotic proteins of the Bcl-2 family are important cancer biomarkers as they are over expressed in all types of cancers (Kelly and Strasser, 2011). Administration of anti-cancer drugs interacting with anti-apoptotic proteins exhibiting no over expression may presumably cause some adverse effect (such as lymphopenia, thrombocytopaenia and anemia) to cancer patients. In these contexts, examining binding affinities and specificities of antagonists to the anti-apoptotic proteins is crucial to avoid/reduce latestage attritions in drug discovery processes. We have studied binding affinities of the HDNB with each anti-apoptotic protein using molecular docking methods and stringently scrutinized mode of interactions of the lead with the proteins. You must attribute the work in the manner specified by the author or licensor
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
