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Virtual screening of RAGE inhibitors using molecular docking.

ABSTRACT: Advanced Glycation End products (AGEs) interaction with Receptor for AGEs (RAGE) activates downstream signaling and evokes inflammatory responses in vascular cells. Therefore, it is of interest to design a novel series of molecules with a library of 352 compounds based on natural Isoflavone and Argpyrimidine moities. The compounds screened against the optimized structure of RAGE (PDB code: 3CJJ) using MolDock aided with molecular docking algorithm. This exercise identified compound number 62 with appreciable ADME properties having no toxicity and pharmacophore features. Therefore, compound 62 identified as a RAGE inhibitor is proposed for further validation in the context of Diabetic Retinopathy (DR) and vascular complications.

SUBMITTER: Devi Alaparthi M

PROVIDER: S-EPMC5267955 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Virtual screening of RAGE inhibitors using molecular docking.

Devi Alaparthi Malini M Gopinath Gudipudi G Bandaru Srinivas S Sankeshi Venu V Mangalarapu Madhavi M Sudha Nagamalla Swetha S Sudhakar Kota K Roja Rani Anupalli A Rao Sagurthi Someswar S

Bioinformation 20160615 3

Advanced Glycation End products (AGEs) interaction with Receptor for AGEs (RAGE) activates downstream signaling and evokes inflammatory responses in vascular cells. Therefore, it is of interest to design a novel series of molecules with a library of 352 compounds based on natural Isoflavone and Argpyrimidine moities. The compounds screened against the optimized structure of RAGE (PDB code: 3CJJ) using MolDock aided with molecular docking algorithm. This exercise identified compound number 62 wit ...[more]

PMID: 28149046

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Project description:Background:In experimental therapy of cancer, survivin is considered to be one of the well-established targets. Studies have found that it is overexpression in most of the human tumors, but it is rarely found in normal tissues. It is having varied structural and functional role. It controls cell division and cellular stress response and also regulates metastasis and migration of cancerous cells. It has also been recognized as a biomarker which makes it unconventional drug target. In spite of being one of the centrally active components in metastasis and invasion, their clinical use is minimal. To increase the therapeutic efficiency of cancer and its various stages, it is important to survey novel reagents targeting the pathways and mechanism involving survivin. Objective:The aim of this study was to identify novel survivin inhibitor candidates using in silico screening. Materials and Methods:In this course of work, virtual screening on a dataset of natural compounds retrieved from ZINC and other libraries were performed. Comparative analysis of the protein was done by studying the binding affinity of inhibitors that are already available. The best interacting complex was set for molecular dynamics simulation for 25 ns to validate the stability of system. These molecules were checked for their toxicity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using OSIRIS and pre-ADMET tools. Results:We discovered ten such candidates with better binding efficiency with survivin in comparison to marketed chemical against the same. Furthermore, these inhibitor candidates did not induce cell toxicity. Binding affinity of reference molecules was varied from -6.8 to -8.5 kcal/mol while that of top scoring compound ZINC00689728 is -9.3 kcal/mol binding energy. Good placement and strong bond formation of selected molecule was observed during course of work. It is also having permissible ADMET property. Conclusion:Considering all the parameters, the screened molecule can be considered as a potential lead compound for designing new drug against survivin. Further investigation and testing will be required to make it to the final stage. SUMMARY:Survivin is one of the important protein of metastasis. Inhibiting survivin might led to the increased therapeutic efficiency of cancer. In this work we are screening library of natural compounds in view of finding some potent inhibitor against survivin. Abbreviations used: MD: Molecular dynamics, LogS: Aqueous solubility, Acceptor HB: Hydrogen bond acceptor, Donor HB: Donor hydrogen bond donor, ADMET: Absorption, distribution, metabolism, excretion, and toxicity, RCSB: Research Collaboratory for Structural Bioinformatics, OPLS: Optimized potentials for liquid simulations, RMSD: Root-mean-square deviation.

Dataset Information

Virtual screening of RAGE inhibitors using molecular docking.

Publications

Virtual screening of RAGE inhibitors using molecular docking.

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