Abstract
A protein's flexibility is well recognized to underlie its capacity to engage in critical functions, such as signal transduction, biomolecular transport and biochemical reactivity. Molecular recognition is also tightly linked to the dynamics of the binding partners, yet protein flexibility has largely been ignored by the growing field of structure-based drug design (SBDD). In combination with experimentally determined structures, a number of computational methods have been proposed to model protein movements, which may be important for small molecule binding. Such techniques have the ability to expose new binding site conformations, which may in turn recognize and lead to the discovery of more potent and selective drugs through molecular docking. In this article, we discuss various methods and focus on the Relaxed Complex Scheme (RCS), which uses Molecular Dynamics (MD) simulations to model full protein flexibility and enhance virtual screening programmes. We review practical applications of the RCS and use a recent study of the HIV-1 reverse transcriptase to illustrate the various phases of the scheme. We also discuss some encouraging developments, aimed at addressing current weaknesses of the RCS.
Keywords: docking, drug discovery, molecular dynamics, virtual screening, biomolecular, flexibility, molecular docking, algorithms, catalysis, crystallographic, inhibitor, non-nucleoside, transcriptase, torsional, cryptic, heterogeneity, nuclear magnetic resonance, cyclin, kinase
Current Pharmaceutical Design
Title: Molecular Recognition in the Case of Flexible Targets
Volume: 17 Issue: 17
Author(s): Anthony Ivetac and J. Andrew McCammon
Affiliation:
Keywords: docking, drug discovery, molecular dynamics, virtual screening, biomolecular, flexibility, molecular docking, algorithms, catalysis, crystallographic, inhibitor, non-nucleoside, transcriptase, torsional, cryptic, heterogeneity, nuclear magnetic resonance, cyclin, kinase
Abstract: A protein's flexibility is well recognized to underlie its capacity to engage in critical functions, such as signal transduction, biomolecular transport and biochemical reactivity. Molecular recognition is also tightly linked to the dynamics of the binding partners, yet protein flexibility has largely been ignored by the growing field of structure-based drug design (SBDD). In combination with experimentally determined structures, a number of computational methods have been proposed to model protein movements, which may be important for small molecule binding. Such techniques have the ability to expose new binding site conformations, which may in turn recognize and lead to the discovery of more potent and selective drugs through molecular docking. In this article, we discuss various methods and focus on the Relaxed Complex Scheme (RCS), which uses Molecular Dynamics (MD) simulations to model full protein flexibility and enhance virtual screening programmes. We review practical applications of the RCS and use a recent study of the HIV-1 reverse transcriptase to illustrate the various phases of the scheme. We also discuss some encouraging developments, aimed at addressing current weaknesses of the RCS.
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Cite this article as:
Ivetac Anthony and Andrew McCammon J., Molecular Recognition in the Case of Flexible Targets, Current Pharmaceutical Design 2011; 17 (17) . https://dx.doi.org/10.2174/138161211796355056
DOI https://dx.doi.org/10.2174/138161211796355056 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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