+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      3D QSAR Pharmacophore Modeling, in Silico Screening, and Density Functional Theory (DFT) Approaches for Identification of Human Chymase Inhibitors


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Human chymase is a very important target for the treatment of cardiovascular diseases. Using a series of theoretical methods like pharmacophore modeling, database screening, molecular docking and Density Functional Theory (DFT) calculations, an investigation for identification of novel chymase inhibitors, and to specify the key factors crucial for the binding and interaction between chymase and inhibitors is performed. A highly correlating ( r = 0.942) pharmacophore model (Hypo1) with two hydrogen bond acceptors, and three hydrophobic aromatic features is generated. After successfully validating “Hypo1”, it is further applied in database screening. Hit compounds are subjected to various drug-like filtrations and molecular docking studies. Finally, three structurally diverse compounds with high GOLD fitness scores and interactions with key active site amino acids are identified as potent chymase hits. Moreover, DFT study is performed which confirms very clear trends between electronic properties and inhibitory activity (IC 50) data thus successfully validating “Hypo1” by DFT method. Therefore, this research exertion can be helpful in the development of new potent hits for chymase. In addition, the combinational use of docking, orbital energies and molecular electrostatic potential analysis is also demonstrated as a good endeavor to gain an insight into the interaction between chymase and inhibitors.

          Related collections

          Most cited references94

          • Record: found
          • Abstract: not found
          • Article: not found

          PHASE: a novel approach to pharmacophore modeling and 3D database searching.

            • Record: found
            • Abstract: found
            • Article: not found

            Binding mechanism of coronavirus main proteinase with ligands and its implication to drug design against SARS ☆

            In order to stimulate the development of drugs against severe acute respiratory syndrome (SARS), based on the atomic coordinates of the SARS coronavirus main proteinase determined recently [Science 13 (May) (2003) (online)], studies of docking KZ7088 (a derivative of AG7088) and the AVLQSGFR octapeptide to the enzyme were conducted. It has been observed that both the above compounds interact with the active site of the SARS enzyme through six hydrogen bonds. Also, a clear definition of the binding pocket for KZ7088 has been presented. These findings may provide a solid basis for subsite analysis and mutagenesis relative to rational design of highly selective inhibitors for therapeutic application. Meanwhile, the idea of how to develop inhibitors of the SARS enzyme based on the knowledge of its own peptide substrates (the so-called “distorted key” approach) was also briefly elucidated.
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              iDNA-Prot: Identification of DNA Binding Proteins Using Random Forest with Grey Model

              DNA-binding proteins play crucial roles in various cellular processes. Developing high throughput tools for rapidly and effectively identifying DNA-binding proteins is one of the major challenges in the field of genome annotation. Although many efforts have been made in this regard, further effort is needed to enhance the prediction power. By incorporating the features into the general form of pseudo amino acid composition that were extracted from protein sequences via the “grey model” and by adopting the random forest operation engine, we proposed a new predictor, called iDNA-Prot, for identifying uncharacterized proteins as DNA-binding proteins or non-DNA binding proteins based on their amino acid sequences information alone. The overall success rate by iDNA-Prot was 83.96% that was obtained via jackknife tests on a newly constructed stringent benchmark dataset in which none of the proteins included has pairwise sequence identity to any other in a same subset. In addition to achieving high success rate, the computational time for iDNA-Prot is remarkably shorter in comparison with the relevant existing predictors. Hence it is anticipated that iDNA-Prot may become a useful high throughput tool for large-scale analysis of DNA-binding proteins. As a user-friendly web-server, iDNA-Prot is freely accessible to the public at the web-site on http://icpr.jci.edu.cn/bioinfo/iDNA-Prot or http://www.jci-bioinfo.cn/iDNA-Prot. Moreover, for the convenience of the vast majority of experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results.

                Author and article information

                Int J Mol Sci
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                12 December 2011
                : 12
                : 12
                : 9236-9264
                [1 ]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), 501 Jinju-daero, Gazwa-dong, Jinju 660-701, Korea; E-Mails: mahr@ 123456bio.gnu.ac.kr (M.A.); sunder@ 123456bio.gnu.ac.kr (S.T.); shalini@ 123456bio.gnu.ac.kr (S.J.); swan@ 123456bio.gnu.ac.kr (S.H.)
                [2 ]Department of Chemistry Education, Research Institute of Natural Science (RINS), Educational Research Institute, Gyeongsang National University, Jinju 660-701, Korea; E-Mail: mc7@ 123456gsnu.ac.kr
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: kwlee@ 123456gnu.ac.kr ; Tel.: +82-55-751-6276; Fax: +82-55-752-7062.

                These authors contributed equally to this work.

                © 2011 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                : 24 October 2011
                : 18 November 2011
                : 23 November 2011

                Molecular biology
                chymase,in silico screening,molecular electrostatic potential,pharmacophore,density functional theory,molecular docking


                Comment on this article