beta-secretase 1 (BACE1) initiates the proteolysis of amyloid precursor protein (APP) to generate AS, aggregation of which has been considered to be the main histopathological feature of Alzheimer's Disease. Here, we have explored the conformational switching of BACE1 during APP recognition using molecular dynamics simulation thereby suggesting the recognition to be a conformational selection process. Free BACE1 is highly flexible and exists as an ensemble of conformations. The beta-hairpin flap that covers the active site of BACE1 visits numerous conformations during the simulation. Essential dynamics reveal that concerted movements in several loops including the flap region lead to a conformational switching from open to closed form. During the simulation, free BACE1 visits both the open and dosed forms multiple times. Binding of APP to the BACE1 cavity shifts the equilibrium towards a stable complex stabilized by strong electrostatic surface complementarity along with several van der Waals and hydrogen bonding interactions. (C) 2015 Elsevier B.V. All rights reserved.

SOUMALEE BASU

Microbiology

SANDIPAN CHAKRABORTY

University of Calcutta (informally known as Calcutta University or CU) is a collegiate public state university located in Kolkata, West Bengal, India.&nbsp;Within India it is recognized as a &quot;Five-Star University&quot; and accredited &quot;A&quot; Grade by National Assessment and Accreditation Council.

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The University of Calcutta has secured the Fifth position among the Universities of India in the prestigious &quot;Indian University Ranking 2019&quot; list, released by the NIRF of the Ministry of Human Resource Development, Government of India.

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It was established on 24 January 1857, and was one of the first institutions in Asia to be established as a multidisciplinary and Western-style university. Its alumni and faculty include several heads of state, heads of government, social reformers, prominent artists, only academy award winner and Dirac medal winner in India, many Fellows of the Royal Society and five Nobel laureates as of 2019 which is highest in South Asia.

University Of Calcutta

Biophysical Chemistry

Mimicking receptor flexibility during receptor-ligand binding is a challenging task in computational drug design since it is associated with a large increase in the conformational search space. In the present study, we have devised an in silico design strategy incorporating receptor flexibility in virtual screening to identify potential lead compounds as inhibitors for flexible proteins. We have considered BACE1 (β-secretase), a key target protease from a therapeutic perspective for Alzheimer's disease, as the highly flexible receptor. The protein undergoes significant conformational transitions from open to closed form upon ligand binding, which makes it a difficult target for inhibitor design. We have designed a hybrid structure-activity model containing both ligand based descriptors and energetic descriptors obtained from molecular docking based on a dataset of structurally diverse BACE1 inhibitors. An ensemble of receptor conformations have been used in the docking study, further improving the prediction ability of the model. The designed model that shows significant prediction ability judged by several statistical parameters has been used to screen an in house developed 3-D structural library of 731 phytochemicals. 24 highly potent, novel BACE1 inhibitors with predicted activity (Ki) ≤ 50 nM have been identified. Detailed analysis reveals pharmacophoric features of these novel inhibitors required to inhibit BACE1. This journal is © the Partner Organisations 2014.

Molecular BioSystems

Encompassing receptor flexibility in virtual screening using ensemble docking-based hybrid QSAR: Discovery of novel phytochemicals for BACE1 inhibition

Acta Crystallographica Section D Biological Crystallography

Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations

Neurochemistry International

Conformational transition in the substrate binding domain of β-secretase exploited by NMA and its implication in inhibitor recognition: BACE1–myricetin a case study

Journal of Biological Chemistry

Amyloid Precursor Protein Trafficking, Processing, and Function

Nucleic Acids Research

PBEQ-Solver for online visualization of electrostatic potential of biomolecules

Structural insight into the mechanism of amyloid precursor protein recognition by beta-secretase 1: A molecular dynamics study

Journal	Data powered by TypesetBiophysical Chemistry
Publisher	Data powered by TypesetELSEVIER SCIENCE BV
ISSN	0301-4622
Open Access	No