Journal ArticleDOI
Homology modeling of 5-lipoxygenase and hints for better inhibitor design.
Reads0
Chats0
TLDR
The homology modeling technique has been used to construct the structure of potato 5-LOX and the results correlated well with the experimental data reported, which proved the quality of the model.Abstract:
Lipoxygenases (LOXs) are a group of enzymes involved in the oxygenation of polyunsaturated fatty acids. Among these 5-lipoxygenase (5-LOX) is the key enzyme leading to the formation of pharmacologically important leukotrienes and lipoxins, the mediators of inflammatory and allergic disorders. In view of close functional similarity to mammalian lipoxygenase, potato 5-LOX is used extensively. In this study, the homology modeling technique has been used to construct the structure of potato 5-LOX. The amino acid sequence identity between the target protein and sequence of template protein 1NO3 (soybean LOX-3) searched from NCBI protein BLAST was 63%. Based on the template structure, the protein model was constructed by using the Homology program in InsightII. The protein model was briefly refined by energy minimization steps and validated using Profile-3D, ERRAT and PROCHECK. The results showed that 99.3% of the amino acids were in allowed regions of Ramachandran plot, suggesting that the model is accurate and its stereochemical quality good. Like all LOXs, 5-LOX also has a two-domain structure, the small N-terminal beta-barrel domain and a larger catalytic domain containing a single atom of non-heme iron coordinating with His525, His530, His716 and Ile864. Asn720 is present in the fifth coordination position of iron. The sixth coordination position faces the open cavity occupied here by the ligands which are docked. Our model of the enzyme is further validated by examining the interactions of earlier reported inhibitors and by energy minimization studies which were carried out using molecular mechanics calculations. Four ligands, nordihydroguaiaretic acid (NDGA) having IC(50) of 1.5 microM and analogs of benzyl propargyl ethers having IC(50) values of 760 microM, 45 microM, and no inhibition respectively were selected for our docking and energy minimization studies. Our results correlated well with the experimental data reported earlier, which proved the quality of the model. This model generated can be further used for the design and development of more potent 5-LOX inhibitors.read more
Citations
More filters
Journal ArticleDOI
Molecular enzymology of lipoxygenases.
Igor Ivanov,Dagmar Heydeck,Katharina Hofheinz,Jana Roffeis,Valerie B. O'Donnell,Hartmut Kühn,Matthias Walther +6 more
TL;DR: This review focuses on recent developments in molecular enzymology ofLOXs and summarizes the current understanding of the structural basis of LOX catalysis, and profiles the existence of LOx-related genomic sequences in the three kingdoms of life.
Journal ArticleDOI
Significance of brain tissue oxygenation and the arachidonic acid cascade in stroke.
Cameron Rink,Savita Khanna +1 more
TL;DR: Two divergent roles of molecular dioxygen in brain tissue are examined as a substrate for life-sustaining homeostatic metabolism of glucose and a substrates for pathogenic metabolism of AA under conditions of stroke.
Journal ArticleDOI
Structure and Ligand Based Drug Design Strategies in the Development of Novel 5-LOX Inhibitors
TL;DR: A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article.
Journal ArticleDOI
Palm oil-derived natural vitamin E alpha-tocotrienol in brain health and disease.
TL;DR: Palm oil–derived α-tocotrienol at nanomolar concentrations has been shown to attenuate both enzymatic and nonenzymatic mediators of AA metabolism and neurodegeneration, representing the most potent of all biological functions exhibited by any natural vitamin E molecule.
Journal ArticleDOI
Recent advances in the search for novel 5-lipoxygenase inhibitors.
TL;DR: An update on 5-LO inhibitors currently under clinical development and the recent advances in the search for novel 5-lipoxygenase inhibitors with a focus on computational methods are summarized.
References
More filters
Journal ArticleDOI
The Protein Data Bank
Helen M. Berman,John D. Westbrook,Zukang Feng,Gary L. Gilliland,Talapady N. Bhat,Helge Weissig,Ilya N. Shindyalov,Philip E. Bourne +7 more
TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Journal ArticleDOI
A general method applicable to the search for similarities in the amino acid sequence of two proteins
TL;DR: A computer adaptable method for finding similarities in the amino acid sequences of two proteins has been developed and it is possible to determine whether significant homology exists between the proteins to trace their possible evolutionary development.
Journal ArticleDOI
Development and validation of a genetic algorithm for flexible docking.
TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.
Journal ArticleDOI
Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology
TL;DR: Important insights into the mechanisms of inflammatory responses, pain, and fever have been gleaned from the current understanding of eicosanoid biology.
Journal ArticleDOI
Verification of protein structures: Patterns of nonbonded atomic interactions
Chris Colovos,Todd O. Yeates +1 more
TL;DR: A novel method for differentiating between correctly and incorrectly determined regions of protein structures based on characteristic atomic interactions is described.