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Flap Dynamics in Aspartic Proteases : A Computational Perspective

Mahanti, Mukul LU ; Bhakat, Soumendranath LU ; Nilsson, Ulf J. LU and Söderhjelm, Pär LU (2016) In Chemical Biology and Drug Design 88(2). p.159-177
Abstract

Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two β-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange... (More)

Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two β-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange molecular dynamics (REMD) and metadynamics, have been used to understand flap dynamics and conformational motions associated with flap movements. This review is intended to summarize the computational progress towards understanding the flap dynamics of proteases and to be a reference for future studies in this field.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
aspartic protease, beta amino secretase, flap, HIV protease, plasmepsin, molecular modelling, Protease
in
Chemical Biology and Drug Design
volume
88
issue
2
pages
19 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:26872937
  • scopus:84960977615
  • scopus:84978116779
ISSN
1747-0285
DOI
10.1111/cbdd.12745
language
English
LU publication?
yes
id
f49c5f6a-9b45-4952-be41-a0e0ca7b8aae (old id 8825621)
date added to LUP
2016-03-11 14:37:34
date last changed
2017-11-19 03:21:35
@article{f49c5f6a-9b45-4952-be41-a0e0ca7b8aae,
  abstract     = {<p>Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two β-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange molecular dynamics (REMD) and metadynamics, have been used to understand flap dynamics and conformational motions associated with flap movements. This review is intended to summarize the computational progress towards understanding the flap dynamics of proteases and to be a reference for future studies in this field.</p>},
  author       = {Mahanti, Mukul and Bhakat, Soumendranath and Nilsson, Ulf J. and Söderhjelm, Pär},
  issn         = {1747-0285},
  keyword      = {aspartic protease,beta amino secretase,flap,HIV protease, plasmepsin,molecular modelling,Protease},
  language     = {eng},
  month        = {08},
  number       = {2},
  pages        = {159--177},
  publisher    = {Wiley-Blackwell},
  series       = {Chemical Biology and Drug Design},
  title        = {Flap Dynamics in Aspartic Proteases : A Computational Perspective},
  url          = {http://dx.doi.org/10.1111/cbdd.12745},
  volume       = {88},
  year         = {2016},
}