Structural Features Underlying the Activity of Benzimidazole Derivatives that Target Phosphopeptide Recognition by the Tandem BRCT Domain of the BRCA1 Protein

Posted: 19 Feb 2020

See all articles by Saranya Giridharan

Saranya Giridharan

Independent

Vadiraj

Institute for Stem Cell Science and Regenerative Medicine (inStem) - CCBT

Jasti Subbarao

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Mamatha B Nijaguna

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Jayaprakash Periyaswamy

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Sanjana Boggaram

Independent

Amol V Shivange

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus

Gayathri Sadasivam

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Muralidhara Padigaru

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Vijay Potluri

Institute for Stem Cell Science and Regenerative Medicine (inStem)

Ashok R Venkitaraman

InStem, CCBT

Kavitha

Institute for Stem Cell Science and Regenerative Medicine (inStem) - CCBT

Date Written: july 23, 2019

Abstract

The tandem BRCT (tBRCT) domains of BRCA1 propagates intracellular signals initiated by DNA damage thereby controlling cell cycle arrest and DNA damage repair. BRCA1 tBRCT recognizes specific phosphorylated binding motif (pSer-X-X-Phe) on target proteins and makes protein-protein interactions (PPI). Our group has recently identified Bractoppin, a benzimidazole derivative as a first selective small-molecule PPI inhibitor of the BRCA1 tBRCT domain. Understanding the structural features that underlie the biochemical and cellular activities of Bractoppin will play a major role in lead optimization and in the realization of future potential for disease therapy. In this study, we first establish the Bractoppin binding pocket on BRCA1 tBRCT by mutations of residues that engage phospho-peptide and sub pockets abutting phospho-peptide binding site. We further showcase the significance of combining multiple structure-guided strategies like GIST analysis and dimer interface analysis in proposing testable hypothesis that lead to the development of wide range of inhibitors with Structure activity relationships. Finally, we show that Bractoppin derivatives engage its cellular target, BRCA1 and abrogate G2 checkpoint, thus interrupting BRCA1 tBRCT-dependent signals evoked by DNA breakage. Overall, we show successful application of complementary computational methodologies to define the structural features at a molecular level for optimization of biochemical and cellular activities of Bractoppin.

Keywords: BRCA1 tBRCT, Protein-Protein Interaction, DNA Damage, GIST

Suggested Citation

Giridharan, Saranya and Kurdekar, Vadiaraj and Subbarao, Jasti and Nijaguna, Mamatha B and Periyaswamy, Jayaprakash and Boggaram, Sanjana and Shivange, Amol V and Sadasivam, Gayathri and Padigaru, Muralidhara and Potluri, Vijay and Venkitaraman, Ashok R and Bharatham, Kavitha, Structural Features Underlying the Activity of Benzimidazole Derivatives that Target Phosphopeptide Recognition by the Tandem BRCT Domain of the BRCA1 Protein (july 23, 2019). https://doi.org/10.1002/cmdc.201900300, Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3540880

Vadiaraj Kurdekar

Institute for Stem Cell Science and Regenerative Medicine (inStem) - CCBT ( email )

NCBS campus, Bellary Road
Bangalore, Karnataka 560097
India

Jasti Subbarao

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Mamatha B Nijaguna

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Jayaprakash Periyaswamy

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Sanjana Boggaram

Independent

Amol V Shivange

Howard Hughes Medical Institute (HHMI) - Chevy Chase - Janelia Research Campus ( email )

19700 Helix Drive
Ashburn, VA 20147
United States

Gayathri Sadasivam

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Muralidhara Padigaru

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Vijay Potluri

Institute for Stem Cell Science and Regenerative Medicine (inStem) ( email )

India

Ashok R Venkitaraman

InStem, CCBT ( email )

Hutchison/MRC Research Centre
Box 197, Cambridge Biomedical Campus
Cambridge, CB2 0XZ
United Kingdom

Kavitha Bharatham

Institute for Stem Cell Science and Regenerative Medicine (inStem) - CCBT ( email )

NCBS campus, Bellary Road
Bangalore, Karnataka 560097
India

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