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      Molecular Dynamics Simulations of Sonic Hedgehog-Receptor and Inhibitor Complexes and Their Applications for Potential Anticancer Agent Discovery

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          The sonic hedgehog (Shh) signaling pathway is necessary for a variety of development and differentiation during embryogenesis as well as maintenance and renascence of diverse adult tissues. However, an abnormal activation of the signaling pathway is related to various cancers. In this pathway, the Shh signaling transduction is facilitated by binding of Shh to its receptor protein, Ptch. In this study, we modeled the 3D structure of functionally important key loop peptides of Ptch based on homologous proteins. Using this loop model, the molecular interactions between the structural components present in the pseudo-active site of Shh and key residues of Ptch was investigated in atomic level through molecular dynamics (MD) simulations. For the purpose of developing inhibitor candidates of the Shh signaling pathway, the Shh pseudo-active site of this interface region was selected as a target to block the direct binding between Shh and Ptch. Two different structure-based pharmacophore models were generated considering the key loop of Ptch and known inhibitor-induced conformational changes of the Shh through MD simulations. Finally two hit compounds were retrieved through a series of virtual screening combined with molecular docking simulations and we propose two hit compounds as potential inhibitory lead candidates to block the Shh signaling pathway based on their strong interactions to receptor or inhibitor induced conformations of the Shh.

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          Most cited references 27

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          Clustal W and Clustal X version 2.0.

          The Clustal W and Clustal X multiple sequence alignment programs have been completely rewritten in C++. This will facilitate the further development of the alignment algorithms in the future and has allowed proper porting of the programs to the latest versions of Linux, Macintosh and Windows operating systems. The programs can be run on-line from the EBI web server: The source code and executables for Windows, Linux and Macintosh computers are available from the EBI ftp site
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            Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.

            Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
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              Molecular dynamics simulations of biomolecules.

              Molecular dynamics simulations are important tools for understanding the physical basis of the structure and function of biological macromolecules. The early view of proteins as relatively rigid structures has been replaced by a dynamic model in which the internal motions and resulting conformational changes play an essential role in their function. This review presents a brief description of the origin and early uses of biomolecular simulations. It then outlines some recent studies that illustrate the utility of such simulations and closes with a discussion of their ever-increasing potential for contributing to biology.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                31 July 2013
                : 8
                : 7
                Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, Republic of Korea
                Wake Forest University, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SH ST KWL. Performed the experiments: SH. Analyzed the data: SH ST. Wrote the paper: SH.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 10
                This research was supported by Basic Science Research Program (2012R1A1A4A01013657), Pioneer Research Center Program (2009-0081539), and Management of Climate Change Program (2010-0029084) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) of Republic of Korea. And this work was also supported by the Next-Generation BioGreen 21 Program (PJ009486) from Rural Development Administration (RDA) of Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biochemistry Simulations
                Drug Discovery
                Biophysics Simulations
                Drug Discovery
                Computational Biology
                Biochemical Simulations
                Biophysic Al Simulations
                Molecular Cell Biology
                Signal Transduction
                Signaling in Selected Disciplines
                Developmental Signaling
                Computational Chemistry
                Molecular Dynamics
                Medicinal Chemistry
                Theoretical Chemistry
                Drugs and Devices
                Drug Research and Development
                Drug Discovery



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