MOLECULAR DOCKING OF ARYL SEMICARBAZONE AND ARYL THIOSEMICARBAZE DERIVATES AGAINST ENZYME KINASES

MOLECULAR DOCKING OF ARYL SEMICARBAZONE AND ARYL THIOSEMICARBAZE DERIVATES AGAINST ENZYME KINASES

• Author
• George Torres de Lima
• Co-authors
• Abner Lins Dantas , Yasmim Meneses Silva , Dalci José Brondani , Rodrigo Ribeiro Alves Caiana , José Rivaldo de Lima , Elizabeth Fernanda de Oliveira Borba , Teresinha Gonçalves da Silva
• Abstract

•  

  MOLECULAR DOCKING OF ARYL SEMICARBAZONE AND ARYL THIOSEMICARBAZE DERIVATES AGAINST ENZYME KINASES

   

  George Torres de Lima¹; Abner Lins Dantas¹; Yasmim Meneses Silva¹; José Dalci Brondani²; Rodrigo Ribeiro Alves Caiana¹; José Rivaldo de Lima¹; Elizabeth Fernanda de Oliveira Borba¹; Teresinha Gonçalves da Silva^1*.

  ¹ Departamento de Antibióticos, Centro de Biociências, Universidade Federal de Pernambuco.

  ² Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco.

   

   

  george.torres@ufpe.br; teresinha.goncalves@ufpe.br

   

  ABSTRACT

  INTRODUCTION: Molecular docking strategies have stood out for investigating the binding affinity and relative orientation between a pharmacological target and a drug candidate, favoring the identification of promising compounds [1,2]. The success of these computational strategies highlights pharmacological targets with therapeutic potential, such as protein kinases [3, 4, 5]. These proteins play important physiological roles, such as gene transcription, cell cycle, cytoskeleton rearrangement, proliferation, differentiation, migration and cell death [6, 7]. Compounds structurally similar to those derived from aryl semicarbazones and aryl thiosemicarbazones have demonstrated the ability to interact with different kinases that are important for the treatment of cancer [4,9]. AIMS: To evaluate in silico, via molecular docking, the activity of two compounds (LSS4 and LSS6) with good cytotoxic activity for tumor cell lines, against kinase enzymes known for their involvement in the process of initiation and progression of cancer: cyclin-dependent kinase 2 (CDK2), tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and casein kinase 1 (CK1?/?), METHODS: Docking obtained from Autodock 4.1, binders prepared from Avogrado 1.2.0 and AutoDockTools-1.5.6 package. Protein structures (.pdb) were obtained from the Protein Data Bank and prepared in AutoDock. Coordinates are defined from the grid box, based on the active site carrying the co-crystallized giants of each enzyme. The established parameters were validated by redocking the co-crystallized giants to calculate the RMSD. Visual interpretation obtained from Discovery Studio. RESULTS AND DISCUSSION: It was possible to perform the visual interpretation and calculation of the degree of three-dimensional similarity existing between the atoms of the molecules from the Root Mean Standard Deviation (RMSD) value, with RMSD values ??obtained of ? 2, which configures as a value acceptable for carrying out the simulations [CDK2 (RMSD 0.47), DYRK1A (RMSD 1.18) and CK1?/? (RMSD 0.44)]. The free energy values ??of the compounds against CDK2, DYRK1A and CK1?/? were calculated and the results showed that the compounds were able to form energetically favorable complexes with the active sites of the addressed protein kinases, presenting low values ??of binding free energies [LSS4: CDK2 (-6.49), DYRK1A (-6.37), CK1?/? (-7.26)], [LSS6: CDK2 (-7.23), DYRK1A (-7.14), CK1? /? (-7.63). CONCLUSION: The low binding free energy values, the absence of unfavorable interactions and the interaction with different amino acid residues point to the potential of these compounds and their derivatives to act as inhibitors of these and/or other protein kinases, corroborating what has been demonstrated in literature for thiosemicarbazones and its analogues, and encourage the development of new studies that may further explore the biological activities of these compounds.

   

  ACKNOWLEDGEMENT: The authors are grateful for the postgraduate scholarships Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE).

   

  Keywords: Molecular dynamics simulation, semicarbazones, kinases

   

  REFERENCES

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• Keywords
• Molecular dynamics simulation, semicarbazones, kinases
• Modality
• Pôster
• Subject Area
• Quimioinformatics, Bioinformatics and TheoreticalChemistry