Molecular dynamics in drug design

Zhao, Hongtao; Caflisch, Amedeo

doi:10.1016/j.ejmech.2014.08.004

Cited by 188 publications

(96 citation statements)

References 65 publications

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“…Molecular dynamics (MD) simulations have become a powerful tool in drug design and discovery [55–57]. Here we apply this approach to refine our structural models of αS fibril, which could be further used in future studies such as virtual screening of potential drugs targeting PD.…”

Section: Methodsmentioning

confidence: 99%

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

Nussinov

2016

European Journal of Medicinal Chemistry

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The aggregates of α-synuclein (αS) are a major pathological hallmark of Parkinson’s disease (PD) making their structure-function relationship important for rational drug design. Yet, the atomic structure of the αS aggregates is unavailable, making it difficult to understand the underlying aggregation mechanism. In this work, based on available experimental data, we examined plausible molecular structures of αS(20/30–110) fibrils for the first time by employing computational approaches. The optimized structure was used to investigate possible interactions with aggregation inhibitors. Our structural models characterize the essential properties of the five-layered fold of the αS fibril. The distribution of the β-strands and the topology of the five β-strands in the relatively stable models are in good agreement with experimental values. In particular, we find that the KTK(E/Q)GV repeat motifs significantly stabilize the αS fibrils. The charged residues within each repeat prefer exposure to the solvent in order to further stabilize the inter-layered interactions by salt-bridges. The organization of the repeat K58T59K60E61Q62V63 between the β2 and β3 layers significantly affects the stability of the non-amyloid-component (NAC) domain. The coupling between the NAC domain and the KTKEGV repeats indicates that both regions can be potential binding sites for inhibitor design. The distinct binding modes of chemical agents that alter αS aggregation highlight the potential of our models in inhibitor design.

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Section: Methodsmentioning

confidence: 99%

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

Nussinov

2016

European Journal of Medicinal Chemistry

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“…When the ligand binding site is already known, MD can be used to generate ensembles of receptor conformations against which site-directed docking can be performed via the 'relaxed complex' scheme [103]. This paradigm of coupling protein dynamics to HTVS through MD is being widely used [104,105]. A relatively new application of MD in drug discovery is for allosteric binding site identification [106].…”

Section: Conformational Ensembles and MD Simulationsmentioning

confidence: 99%

Computational allosteric ligand binding site identification on Ras proteins

McCarthy

Prakash

Gorfe

2016

ABBS

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A number of computational techniques have been proposed to expedite the process of allosteric ligand binding site identification in inherently flexible and hence challenging drug targets. Some of these techniques have been instrumental in the discovery of allosteric ligand binding sites on Ras proteins, a group of elusive anticancer drug targets. This review provides an overview of these techniques and their application to Ras proteins. A summary of molecular docking and binding site identification is provided first, followed by a more detailed discussion of two specific techniques for binding site identification in ensembles of Ras conformations generated by molecular simulations.

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“…A set of new techniques based on formalisms such as quantum mechanics [5], molecular mechanics [6], molecular dynamics [7], docking [8], scoring and pharmacophore analysis [9], also began to spread. Frequently referred to as 'rational design' approaches, although the expression 'directed design' techniques would be probably more accurate [10], they are now commonly used in drug discovery, especially for disclosing the information related to the drug--receptor interactions.…”

Section: Introductionmentioning

confidence: 99%

Latest advances in molecular topology applications for drug discovery

Zanni

Gálvez-Llompart

García-Domènech

et al. 2015

Expert Opinion on Drug Discovery

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Recent years have witnessed a remarkable rise in QSAR methods based on MT and its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topological indices, such as Bourgas' descriptors and other new concepts as the derivative of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors' opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery.

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Molecular dynamics in drug design

Cited by 188 publications

References 65 publications

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

Computational allosteric ligand binding site identification on Ras proteins

Latest advances in molecular topology applications for drug discovery

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