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Molecular docking analysis of aplysin analogs targeting survivin protein.

ABSTRACT: Survivin (IAP proteins) remains an important target for anticancer drug development as it is reported to be over-expressed in tumor cells to enhance resistance to apoptotic stimuli. The study focuses on virtual screening of marine compounds inhibiting survivin, a multifunctional protein, using a computational approach. Structures of compounds were prepared using ChemDraw Ultra 10. Software and converted into its 3D PDB structure and its energy was minimized using Discovery Studio client 2.5. The target protein, survivin was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling was carried out on marine compounds and the filtered compounds were further promoted for molecular docking analysis and interaction studies using AutoDock Tools 4.0. Molecular docking results revealed that analog (AP 4) of Aplysin, showed very promising inhibitory potential against survivin with a binding energy of -8.75 kcal/mol and Ki 388.28 nM as compared to its known inhibitor, Celecoxib having binding energy of -6.65 kcal/mol and Ki 13.43 ?M. AP 4. The analog depicted similarity in pattern when compared to standard. The result proposes AP 4, is an effective molecule exhibiting prominent potential to inhibit survivin and thus promoting apoptosis in tumor cells.

SUBMITTER: Shakeel E

PROVIDER: S-EPMC5651222 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Molecular docking analysis of aplysin analogs targeting survivin protein.

Shakeel Eram E Akhtar Salman S Khan Mohd Kalim Ahmad MKA Lohani Mohtashim M Arif Jamal M JM Siddiqui Mohd Haris MH

Bioinformation 20170930 9

Survivin (IAP proteins) remains an important target for anticancer drug development as it is reported to be over-expressed in tumor cells to enhance resistance to apoptotic stimuli. The study focuses on virtual screening of marine compounds inhibiting survivin, a multifunctional protein, using a computational approach. Structures of compounds were prepared using ChemDraw Ultra 10. Software and converted into its 3D PDB structure and its energy was minimized using Discovery Studio client 2.5. The ...[more]

PMID: 29081608

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Project description:BackgroundIn 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.ObjectiveThe aim of this study was to identify novel survivin inhibitor candidates using in silico screening.Materials and methodsIn 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.ResultsWe 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.ConclusionConsidering 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.SummarySurvivin 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.

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Molecular docking analysis of aplysin analogs targeting survivin protein.

Publications

Molecular docking analysis of aplysin analogs targeting survivin protein.

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