A leishmaniasis study: Structure-based screening and molecular dynamics mechanistic analysis for discovering potent inhibitors of spermidine synthase

被引:31
作者
Grover, Abhinav [1 ]
Katiyar, Shashank Prakash [1 ]
Singh, Sanjeev Kumar [2 ]
Dubey, Vikash Kumar [3 ]
Sundar, Durai [1 ]
机构
[1] Indian Inst Technol IIT Delhi, Dept Biochem Engn & Biotechnol, New Delhi 110016, India
[2] Alagappa Univ, Dept Bioinformat, Karaikkudi 630003, Tamil Nadu, India
[3] Indian Inst Technol Guwahati, Dept Biotechnol, Gauhati 781039, Assam, India
来源
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2012年 / 1824卷 / 12期
关键词
Leishmania; Spermidine synthase; Inhibitors; Docking; Molecular dynamics simulations; POLYAMINE BIOSYNTHETIC-ENZYMES; MULTIPLE SEQUENCE ALIGNMENT; CRYSTAL-STRUCTURE; PSI-BLAST; PLASMODIUM-FALCIPARUM; ALPHA-DIFLUOROMETHYLORNITHINE; SURFACE-TOPOGRAPHY; ACCURATE DOCKING; PROTEIN MODELS; COMPUTED ATLAS;
D O I
10.1016/j.bbapap.2012.05.016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Protozoa Leishmania donovani (Ld) is the main cause of the endemic disease leishmaniasis. Spermidine synthase (SS), an important enzyme in the synthetic pathway of polyamines in Ld, is an essential element for the survival of this protozoan. Targeting SS may provide an important aid for the development of drugs against Ld. However, absence of tertiary structure of spermidine synthase of Leishmania donovani (LSS) limits the possibilities of structure based drug designing. Presence of the same enzyme in the host itself further challenges the drug development process. We modeled the tertiary structure of LSS using homology modeling approach making use of homologous X-ray crystallographic structure of spermidine synthase of Trypanosoma cruzi (TSS) (2.5 angstrom resolution). The modeled structure was stabilized using Molecular Dynamics simulations. Based on active site structural differences between LSS and human spermidine synthase (HSS), we screened a large dataset of compounds against modeled protein using Glide virtual screen docking and selected two best inhibitors based on their docking scores (-10.04 and -13.11 respectively) with LSS and having least/no binding with the human enzyme. Finally Molecular Dynamics simulations were used to assess the dynamic stability of the ligand bound structures and to elaborate on the binding modes. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction. (C) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:1476 / 1483
页数:8
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