Article

Structure-Based Prediction with Molecular Dynamics for Hit Identification.

University of California, San Diego Howard Hughes Medical Institute 9500 Gilman Drive Urey Hall 4202, M/C 0365 La Jolla, CA 92093-0365. .
Current topics in medicinal chemistry (Impact Factor: 4.47). 10/2012; DOI: 10.2174/156802612804910313
Source: PubMed

ABSTRACT Although the motions of proteins are fundamental for their function, for pragmatic reasons, the consideration of protein elasticity has traditionally been neglected in drug discovery and design. This review details protein motion, its relevance to biomolecular interactions and how it can be sampled using molecular dynamics simulations. Within this context, two major areas of research in structure-based prediction that can benefit from considering protein flexibility, binding site detection and molecular docking, are discussed. Basic classification metrics and statistical analysis techniques, which can facilitate performance analysis, are also reviewed. With hardware and software advances, molecular dynamics in combination with traditional structure-based prediction methods can potentially reduce the time and costs involved in the hit identification pipeline.

0 Bookmarks
 · 
94 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The proper understanding of biomolecular recognition mechanisms that take place in a drug target is of paramount importance to improve the efficiency of drug discovery and development. The intrinsic dynamic character of proteins has a strong influence on biomolecular recognition mechanisms and models such as conformational selection have been widely used to account for this dynamic association process. However, conformational changes occurring in the receptor prior and upon association with other molecules are diverse and not obvious to predict when only a few structures of the receptor are available. In view of the prominent role of protein flexibility in ligand binding and its implications for drug discovery, it is of great interest to identify receptor conformations that play a major role in biomolecular recognition before starting rational drug design efforts. In this review, we discuss a number of recent advances in computer-aided drug discovery techniques that have been proposed to incorporate receptor flexibility into structure-based drug design. The allowance for receptor flexibility provided by computational techniques such as molecular dynamics simulations or enhanced sampling techniques helps to improve the accuracy of methods used to estimate binding affinities and, thus, such methods can contribute to the discovery of novel drug leads.
    Biophysical chemistry 01/2013; · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, to accommodate receptor flexibility, based on multiple receptor conformations (MRC), a novel ensemble docking protocol was developed by using the naïve Bayesian classification technique, and evaluated in terms of the prediction accuracy of docking-based virtual screening (VS) to three important targets in the kinase family, including ALK, CDK2 and VEGFR2. First, for each target, the representative crystal structures were selected by structural clustering, and the capability of molecular docking based on each representative structure to discriminate inhibitors from non-inhibitors was examined. Then, for each target, 50 ns molecular dynamics (MD) simulations were carried out to generate an ensemble of the conformations, and multiple representative structures/snapshots were extracted from each MD trajectory by structural clustering. On average, the representative crystal structures outperform the representative structures extracted from MD simulations in terms of the capabilities to separate inhibitors from non-inhibitors. Finally, by using the naïve Bayesian classification (NBC) technique, an integrated virtual screening strategy was developed to combine the prediction results of molecular docking based on different representative conformations chosen from crystal structures and MD trajectories. It was encouraging to observe that the integrated VS strategy yields better performance than the docking-based VS based on any single rigid conformation. The novel protocol may provide an improved way over existing strategies to search for more diverse and promising active compounds for a target of interest.
    Journal of Chemical Information and Modeling 10/2014; 54(10):2664-2679. · 4.07 Impact Factor

Preview

Download
2 Downloads
Available from