Computational analysis of BACE1-ligand complex crystal structures and linear discriminant analysis for identification of BACE1 inhibitors with anti P-glycoprotein binding property

Abstract

More than 100 years of research on Alzheimer’s disease didn’t yield a potential cure for this dreadful disease. Poor Blood Brain Barrier (BBB) permeability and P-glycoprotein binding of BACE1 inhibitors are the major causes for the failure of these molecules during clinical trials. The design of BACE1 inhibitors with a balance of sufficient affinity to the binding site and little or no interaction with P-glycoproteins is indispensable. Identification and understanding of protein–ligand interactions are essential for ligand optimization process. Structure-based drug design (SBDD) efforts led to a steady accumulation of BACE1-ligand crystal complexes in the PDB. This study focuses on analyses of 153 BACE1-ligand complexes for the direct contacts (hydrogen bonds and weak interactions) observed between protein and ligand and indirect contacts (water-mediated hydrogen bonds), observed in BACE1-ligand complex crystal structures. Intraligand hydrogen bonds were analyzed, with focus on ligand P-glycoprotein efflux. The interactions are dissected specific to subsites in the active site and discussed. The observed protein-ligand and intraligand interactions were used to develop the linear discriminant model for the identification of BACE1 inhibitors with less or no P-glycoprotein binding property. Excellent statistical results and model’s ability to correctly predict a new data-set with an accuracy of 92% is achieved. The results are retrospectively analyzed to give input for the design of potential BACE1 inhibitors.

Keywords:

• BACE1
• hydrogen bond
• structure-based drug design
• weak interactions
• Alzheimer’s disease
• intraligand hydrogen bond
• protein–ligand interactions

Acknowledgement

Nanda Ghoshal (Emeritus Scientist, CSIR) thanks CSIR, New Delhi for providing financial support. Manoharan Prabhu thanks CSIR for Senior Research Fellowship. Chennoju Kiranmai thanks Ministry of Chemicals & Fertilizers for scholarship. M. Prabu thanks Retired Prof. S. Krishnawamy (UGC Dr-D.S. Kothari Postdoctoral mentor) for giving permission to carryout revision work at CoE in Bioinformatics, School of Biotechnology, Madurai Kamaraj University.