Identification of potential Aurora kinase-C protein inhibitors: an amalgamation of energy minimization, virtual screening, prime MMGBSA and AutoDock

Abstract Genomic instability is a trademark of cancer evolution, there is still a wide necessity to discover safe and effective anti-cancer drugs. Aurora kinase-C protein is a member of the Aurora kinase family involved in regulating mitosis phases of the cell cycle. Aurora kinase-C protein has an aberrant expression at spindle assembly checkpoint leading to human cervical cancer and colorectal cancer. Knowledge of 3D structure of the protein is vital for identify possible inhibitors. In the present study, 3D structure prediction of Aurora kinase-C protein is taken up by using comparative homology modeling techniques and minimized by NAMD-VMD Software. The quality of modeled protein was validated using ProSA and Ramachandran plot. Probable binding site in protein was identified from SiteMap and molecular docking based virtual screening was carried out using Asinex database to identify lead molecules. The obtained lead molecules were further optimized using PrimeMM-GBSA and AutoDock. ADME properties of the leads were calculated to ascertain the drug-like properties at lead molecules. Communicated by Ramaswamy H. Sarma

[1]  Radka Svobodová Vařeková,et al.  PDBsum: Structural summaries of PDB entries , 2017, Protein science : a publication of the Protein Society.

[2]  P. Karplus,et al.  A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins , 2010, Biomolecular concepts.

[3]  Christian Cole,et al.  JPred4: a protein secondary structure prediction server , 2015, Nucleic Acids Res..

[4]  Arthur J. Olson,et al.  Automated Docking with Protein Flexibility in the Design of Femtomolar "Click Chemistry" Inhibitors of Acetylcholinesterase , 2013, J. Chem. Inf. Model..

[5]  Thomas A. Halgren,et al.  Identifying and Characterizing Binding Sites and Assessing Druggability , 2009, J. Chem. Inf. Model..

[6]  K. Bhargavi,et al.  Homology Modeling and Docking Studies of Human Bcl-2L10 Protein , 2010, Journal of biomolecular structure & dynamics.

[7]  M Arbyn,et al.  Worldwide burden of cervical cancer in 2008. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[8]  Manfred J. Sippl,et al.  Thirty years of environmental health research--and growing. , 1996, Nucleic Acids Res..

[9]  Ben M. Webb,et al.  Comparative Protein Structure Modeling Using MODELLER , 2007, Current protocols in protein science.

[10]  Z. Xiang,et al.  Advances in homology protein structure modeling. , 2006, Current protein & peptide science.

[11]  J. T. Tseng,et al.  Overexpression of Aurora-C interferes with the spindle checkpoint by promoting the degradation of Aurora-B , 2014, Cell Death and Disease.

[12]  Paulette Roberts,et al.  A fresh look. , 2005, AHP journal.

[13]  Jian Peng,et al.  Template-based protein structure modeling using the RaptorX web server , 2012, Nature Protocols.

[14]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[15]  V. Yang,et al.  Mitotic origins of chromosomal instability in colorectal cancer , 2007, Current colorectal cancer reports.

[16]  N. S. Zefirov,et al.  MM-GBSA and MM-PBSA performance in activity evaluation of AMPA receptor positive allosteric modulators , 2018, Journal of biomolecular structure & dynamics.

[17]  S. Sundar,et al.  Developing imidazole analogues as potential inhibitor for Leishmania donovani trypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach , 2015, Journal of biomolecular structure & dynamics.

[18]  Yahya Sefidbakht,et al.  Homology modeling and molecular dynamics study on Schwanniomyces occidentalis alpha-amylase , 2017, Journal of biomolecular structure & dynamics.

[19]  Paul D Lyne,et al.  Structure-based virtual screening: an overview. , 2002, Drug discovery today.

[20]  Pradeep Kota,et al.  Automated minimization of steric clashes in protein structures , 2011, Proteins.

[21]  Anthony K. Felts,et al.  Identification of Alternative Binding Sites for Inhibitors of HIV-1 Ribonuclease H Through Comparative Analysis of Virtual Enrichment Studies , 2011, J. Chem. Inf. Model..

[22]  Xin Zhang.  Aurora kinases , 2008, Current Biology.

[23]  Klaus Schulten,et al.  Implementation of Accelerated Molecular Dynamics in NAMD. , 2011, Computational science & discovery.

[24]  Freddie R Salsbury,et al.  Molecular dynamics simulations of protein dynamics and their relevance to drug discovery. , 2010, Current opinion in pharmacology.

[25]  Sarita Rajender Potlapally,et al.  Identification of novel leads applying in silico studies for Mycobacterium multidrug resistant (MMR) protein , 2014, Journal of biomolecular structure & dynamics.

[26]  Laxmikant V. Kalé,et al.  Scalable molecular dynamics with NAMD , 2005, J. Comput. Chem..

[27]  Sree Kanth Sivan,et al.  Identification of novel anti cancer agents by applying insilico methods for inhibition of TSPO protein , 2017, Comput. Biol. Chem..

[28]  R. Medema,et al.  The chromosomal passenger complex: guiding Aurora-B through mitosis , 2006, The Journal of cell biology.

[29]  K. Schindler,et al.  Functions of Aurora kinase C in meiosis and cancer , 2015, Front. Cell Dev. Biol..

[30]  Lucía Pérez-Regidor,et al.  Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators , 2016, International journal of molecular sciences.

[31]  David Baker,et al.  Protein homology model refinement by large-scale energy optimization , 2018, Proceedings of the National Academy of Sciences.

[32]  L. Dardenne,et al.  Receptor–ligand molecular docking , 2013, Biophysical Reviews.

[33]  Maria Jesus Martin,et al.  The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003 , 2003, Nucleic Acids Res..

[34]  David S. Goodsell,et al.  AutoDockFR: Advances in Protein-Ligand Docking with Explicitly Specified Binding Site Flexibility , 2015, PLoS Comput. Biol..

[35]  W. Earnshaw,et al.  Chromosomal passengers: the four-dimensional regulation of mitotic events , 2004, Chromosoma.

[36]  Novel aromatase inhibitors selection using induced fit docking and extra precision methods: Potential clinical use in ER-alpha-positive breast cancer , 2016, Bioinformation.

[37]  Francisco Adasme-Carreño,et al.  Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations , 2016, Journal of Computer-Aided Molecular Design.

[38]  Nathan Brown,et al.  Best of Both Worlds: On the Complementarity of Ligand-Based and Structure-Based Virtual Screening , 2014, J. Chem. Inf. Model..

[39]  Shu Liu,et al.  Superimposing the 27 crystal protein/inhibitor complexes of β-secretase to calculate the binding affinities by the linear interaction energy method. , 2010, Bioorganic & medicinal chemistry letters.

[40]  Nathan Brown,et al.  Druggability Analysis and Structural Classification of Bromodomain Acetyl-lysine Binding Sites , 2012, Journal of medicinal chemistry.

[41]  Woody Sherman,et al.  Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments , 2013, Journal of Computer-Aided Molecular Design.

[42]  Stephen L. Mayo,et al.  GRID: A high‐resolution protein structure refinement algorithm , 2013, J. Comput. Chem..

[43]  Tom Halgren,et al.  New Method for Fast and Accurate Binding‐site Identification and Analysis , 2007, Chemical biology & drug design.

[44]  W. Earnshaw,et al.  The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis , 2012, Nature Reviews Molecular Cell Biology.

[45]  Stephen S. Taylor,et al.  Aurora-kinase inhibitors as anticancer agents , 2004, Nature Reviews Cancer.

[46]  Robert D Clark.  Predicting mammalian metabolism and toxicity of pesticides in silico , 2018, Pest management science.

[47]  Ben M. Webb,et al.  Comparative Protein Structure Modeling Using MODELLER , 2016, Current protocols in bioinformatics.

[48]  G. N. Sastry,et al.  Cooperativity in Noncovalent Interactions. , 2016, Chemical reviews.

[49]  Claudio N. Cavasotto,et al.  Docking-based virtual screening for ligands of G protein-coupled receptors: not only crystal structures but also in silico models. , 2011, Journal of molecular graphics & modelling.

[50]  L. Regan,et al.  LETTER TO THE EDITOR Reply to: Comment on ''Revisiting the Ramachandran plot from a new angle'' , 2011 .

[51]  Weida Tong,et al.  Homology modeling, molecular docking, and molecular dynamics simulations elucidated α-fetoprotein binding modes , 2013, BMC Bioinformatics.

[52]  S. Genheden,et al.  The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities , 2015, Expert opinion on drug discovery.

[53]  Jun Hu,et al.  ATPbind: Accurate Protein-ATP Binding Site Prediction by Combining Sequence-Profiling and Structure-Based Comparisons , 2018, J. Chem. Inf. Model..

[54]  Tjaart A. P. de Beer,et al.  Protein homology modelling and its use in South Africa , 2008 .

[55]  G Narahari Sastry,et al.  Virtual high throughput screening in new lead identification. , 2011, Combinatorial chemistry & high throughput screening.

[56]  T. Prueksaritanont,et al.  ADME of Biologics—What Have We Learned from Small Molecules? , 2012, The AAPS Journal.