Autophagy has drawn attention from the scientific community, mainly because of its significant advantages over chemotherapeutic processes. One of these advantages is its direct action on cancer cells, avoiding possible side effects, unlike chemotherapy, which reaches tumor cells and affects healthy cells in the body, leading to a great loss in the quality of life of patients. In this way, it is known that vanadium complex (VC) [VO(oda)(phen)] has proven inhibition effect on autophagy process in pancreatic cancer cells. Keeping that in mind, molecular dynamics (MD) simulations can be considered excellent strategies to investigate the interaction of metal complexes and their biological targets. However, simulations of this type are strongly dependent on the appropriate choice of force field (FF). Therefore, this work proposes the development of AMBER FF parameters for VC, having a minimum energy structure as a starting point, obtained through DFT calculations with B3LYP/def2-TZVP level of theory plus ECP for the vanadium atom. An MD simulation in vacuum was performed to validate the developed FF. From the structural analyses, satisfying values of VC bond lengths and angles were obtained, where a good agreement with the experimental data and the quantum reference was found. The RMSD analysis showed an average of only 0.3%. Finally, we performed docking and MD (120 ns) simulations with explicit solvent between VC and PI3K. Overall, our findings encourage new parameterizations of metal complexes with significant biological applications, as well as allow to contribute to the elucidation of the complex process of autophagy.

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Institute of Chemistry University of Campinas SP Campinas 13083 970 Brazil

Laboratory of Molecular Modelling Department of Chemistry Federal University of Lavras MG Lavras 37200 000 Brazil

See more in PubMed

Pham Q, et al. Artificial intelligence (AI) and big data for coronavirus (COVID-19) pandemic: a survey on the state-of-the-arts. Ieee Access. 2020;4:1–19. PubMed PMC

Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. PubMed

Shah UA. Cancer and coronavirus disease 2019 (COVID-19)—facing the “C words”. JAMA Oncol. 2020;6(9):1330–1331. PubMed

Golčić M, et al. Could fecal microbial transplantation offer a new potential in the treatment of metastatic pancreatic ductal adenocarcinoma? Med Hypotheses. 2022;161:110801.

Gasic U, et al. Polyphenols as possible agents for pancreatic diseases. Antioxidants. 2020;9(6):547. PubMed PMC

Cheng X, Zhao G, Zhao Y (2018) Combination immunotherapy approaches for pancreatic cancer treatment. Can J Gastroenterol Hepatol 2018 PubMed PMC

Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17(8):487–505. PubMed PMC

Jin J, Teng C, Li T. Combination therapy versus gemcitabine monotherapy in the treatment of elderly pancreatic cancer: a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:475. PubMed PMC

Petruczynik A, et al. Comparison of anticancer activity and HPLC-DAD determination of selected isoquinoline alkaloids from Thalictrum foetidum, Berberis sp. and Chelidonium majus extracts. Molecules. 2019;24(19):3417. PubMed PMC

Haque A, Brazeau D, Amin A. Perspectives on natural compounds in chemoprevention and treatment of cancer: an update with new promising compounds. Eur J Cancer. 2021;149:165–183. PubMed PMC

Zuo W, Kwok H. Development of marine-derived compounds for cancer therapy. Mar Drugs. 2021;19(6):342. PubMed PMC

Sheng R, Qin Z. Autophagy: biology and diseases. Singapore: Springer; 2019. History and current status of autophagy research; pp. 3–37. PubMed

Frake RA, Rubinsztein D. Yoshinori Ohsumi’s Nobel prize for mechanisms of autophagy: from basic yeast biology to therapeutic potential. J R Coll Physicians Edinb. 2016;46(4):228–233. PubMed

Shi S, et al. Effects of tetrahedral DNA nanostructures on autophagy in chondrocytes. Chem Commun. 2018;54(11):1327–1330. PubMed

Czaja MJ. Function of autophagy in nonalcoholic fatty liver disease. Dig Dis Sci. 2016;61(5):1304–1313. PubMed PMC

Shi Q, et al. Mechanisms of action of autophagy modulators dissected by quantitative systems pharmacology analysis. Int J Mol Sci. 2020;21(8):2855. PubMed PMC

Campos-Blázquez, J. et al. Relationship between ROS, autophagy, and cancer. 2022

Cui B, Yu J. Autophagy: a new pathway for traditional Chinese medicine. J Asian Nat Prod Res. 2018;20(1):14–26. PubMed

Xiao Z, et al. Autophagy promotion enhances the protective effect of Morroniside on human OA chondrocyte. Biosci Biotechnol Biochem. 2020;84(5):989–996. PubMed

Yang A, Hacheney I, Wu Y. Semisynthesis of autophagy protein LC3 conjugates. Bioorg Med Chem. 2017;25(18):4971–4976. PubMed

Suzuki H, et al. Structural biology of the core autophagy machinery. Curr Opin Struct Biol. 2017;43:10–17. PubMed

Su R, et al. Particulate matter exposure induces the autophagy of macrophages via oxidative stress-mediated PI3K/AKT/mTOR pathway. Chemosphere. 2017;167:444–453. PubMed

Lin C, et al. Honokiol induces autophagic cell death in malignant glioma through reactive oxygen species-mediated regulation of the p53/PI3K/Akt/mTOR signaling pathway. Toxicol Appl Pharmacol. 2016;304:59–69. PubMed

Le Sage V, et al. Adapting the stress response: viral subversion of the mTOR signaling pathway. Viruses. 2016;8(6):152. PubMed PMC

Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018;19(6):349–364. PubMed

Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913–1930. PubMed PMC

Kocak M, et al. Targeting autophagy in disease: established and new strategies. Autophagy. 2021;18:1–23. PubMed PMC

El-Shafey ES, Elsherbiny ES. Possible selective cytotoxicity of vanadium complex on breast cancer cells involving pathophysiological pathways. Anti-Cancer Agents Med Chem (formerly current medicinal chemistry-anti-cancer agents) 2019;19(17):2130–2139. PubMed

Sutradhar M, et al. Antiproliferative activity of heterometallic sodium and potassium-dioxidovanadium (V) polymers. J Inorg Biochem. 2019;200:110811. PubMed

Kowalski S, et al. New oxidovanadium (IV) coordination complex containing 2-methylnitrilotriacetate ligands induces cell cycle arrest and autophagy in human pancreatic ductal adenocarcinoma cell lines. Int J Mol Sci. 2019;20(2):261. PubMed PMC

Kowalski S, et al. Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process. Oncotarget. 2017;8(36):60324. PubMed PMC

Huang Y, et al. Vanadium (IV)-chlorodipicolinate alleviates hepatic lipid accumulation by inducing autophagy via the LKB1/AMPK signaling pathway in vitro and in vivo. J Inorg Biochem. 2018;183:66–76. PubMed

Machado PA, et al. VOSalophen: a vanadium complex with a stilbene derivative—induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis. JBIC J Biol Inorg Chem. 2017;22(6):929–939. PubMed

Walker CL, et al. Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy, and enhances recovery following cervical spinal cord injury. PLoS One. 2012;7(1):e30012. PubMed PMC

Wu Y, et al. Sodium orthovanadate inhibits growth of human hepatocellular carcinoma cells in vitro and in an orthotopic model in vivo. Cancer Lett. 2014;351(1):108–116. PubMed

Lin F, Wang R. Systematic derivation of AMBER force field parameters applicable to zinc-containing systems. J Chem Theory Comput. 2010;6(6):1852–1870. PubMed

Kashefolgheta S, Verde AV. Developing force fields when experimental data is sparse: AMBER/GAFF-compatible parameters for inorganic and alkyl oxoanions. Phys Chem Chem Phys. 2017;19(31):20593–20607. PubMed

Islam M, et al. Interactions of hydrogen with the iron and iron carbide interfaces: a ReaxFF molecular dynamics study. Phys Chem Chem Phys. 2016;18(2):761–771. PubMed

Rogacka J, et al. Intermediate states approach for adsorption studies in flexible metal–organic frameworks. Phys Chem Chem Phys. 2019;21(6):3294–3303. PubMed

Hu L, Ryde U. Comparison of methods to obtain force-field parameters for metal sites. J Chem Theory Comput. 2011;7(8):2452–2463. PubMed

Taylor-Edinbyrd K, Li T, Kumar R. Effect of chemical structure of S-nitrosothiols on nitric oxide release mediated by the copper sites of a metal organic framework based environment. Phys Chem Chem Phys. 2017;19(19):11947–11959. PubMed

Prandi IG, et al. Combining classical molecular dynamics and quantum mechanical methods for the description of electronic excitations: the case of carotenoids. J Comput Chem. 2016;37(11):981–991. PubMed

Álvarez L, et al. Comparison of the coordination capabilities of thiodiacetate and oxydiacetate ligands through the X-ray characterization and DFT studies of [V (O)(tda)(phen)]· 4H2O and [V (O)(oda)(phen)]· 1.5 H2O. Polyhedron. 2010;29(16):3028–3035.

Kaur N, et al. Spin inversion phenomenon and two-state reactivity mechanism for direct benzene hydroxylation by V4O10 cluster. J Phys Chem A. 2016;120(48):9588–9597. PubMed

Kaur N, Gupta S, Goel N. Enantioselective synthesis of sulfoxide using an SBA-15 supported vanadia catalyst: a computational elucidation using a QM/MM approach. Phys Chem Chem Phys. 2017;19(36):25059–25070. PubMed

Frisch MJ, et al. Gaussian 09, Revision E.01. Wallingford CT: Gaussian, Inc.; 2013.

Neese F. Software update: the ORCA program system, version 4.0. Wiley Interdisciplinary Reviews: Computational Molecular. Science. 2017;8(1):e1327.

Cárdenas G, et al. A force field for a manganese-vanadium water oxidation catalyst: redox potentials in solution as showcase. Catalysts. 2021;11(4):493.

Cornell WD, et al. Application of RESP charges to calculate conformational energies, hydrogen bond energies, and free energies of solvation. J Am Chem Soc. 2002;115(21):9620–9631.

Seminario JM. Calculation of intramolecular force fields from second-derivative tensors. Int J Quantum Chem. 1996;60(7):1271–1277.

Mayne CG, et al. Rapid parameterization of small molecules using the force field toolkit. J Comput Chem. 2013;34(32):2757–2770. PubMed PMC

Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(1):33–38. PubMed

Case DA, et al. Amber 2021. São Francisco: University of California; 2021.

Salmaso V, Moro S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: an overview. Front Pharmacol. 2018;9:923. PubMed PMC

Pereira AF, Prandi IG, Ramalho TC. Parameterization and validation of a new force field for Pt (II) complexes of 2-(4′-amino-2′-hydroxyphenyl) benzothiazole. Int J Quantum Chem. 2021;121(6):e26525.

Cousins KR. Computer review of ChemDraw Ultra 12.0. J Am Chem Soc. 2011;133:8388. PubMed

Wang J, et al. Development and testing of a general amber force field. J Comput Chem. 2004;25(9):1157–1174. PubMed

Sebesta F, et al. Estimation of transition-metal empirical parameters for molecular mechanical force fields. J Chem Theory Comput. 2016;12(8):3681–3688. PubMed

D’Angelo ND, et al. Discovery and optimization of a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors. J Med Chem. 2011;54(6):1789–1811. PubMed

Waterhouse A, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296–W303. PubMed PMC

Martínez L, Andreani R, Martínez JM. Convergent algorithms for protein structural alignment. BMC Bioinformatics. 2007;8(1):1–15. PubMed PMC

Thomsen R, Christensen MH. MolDock: a new technique for high-accuracy molecular docking. J Med Chem. 2006;49(11):3315–3321. PubMed

Gurumoorthy P, Mahendiran D, Rahiman AK. Theoretical calculations, DNA interaction, topoisomerase I and phosphatidylinositol-3-kinase studies of water soluble mixed-ligand nickel (II) complexes. Chem Biol Interact. 2016;248:21–35. PubMed

Case DA, et al. The Amber biomolecular simulation programs. J Comput Chem. 2005;26(16):1668–1688. PubMed PMC

Arba M, Sufriadin M, Tjahjono DH. Identification of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor: pharmacophore-based virtual screening and molecular dynamics simulation. Indian J Chem. 2020;20(5):1070–1079.

Farrokhzadeh A, Akher FB, Egan TJ. Molecular mechanism exploration of potent fluorinated PI3K inhibitors with a triazine scaffold: unveiling the unusual synergistic effect of pyridine-to-pyrimidine ring interconversion and CF3 defluorination. J Phys Chem B. 2021;125(36):10072–10084. PubMed

Jorgensen WL, et al. Comparison of simple potential functions for simulating liquid water. J Chem Phys. 1983;79(2):926–935.

Ryckaert JP, Ciccotti G, Berendsen HJC. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys. 1977;23(3):327–341.

Darden T, York D, Pedersen L. Particle mesh Ewald: An N· log (N) method for Ewald sums in large systems. J Chem Phys. 1993;98(12):10089–10092.

Izaguirre JA, et al. Langevin stabilization of molecular dynamics. J Chem Phys. 2001;114(5):2090–2098.

Roe DR, Cheatham TE., III PTRAJ and CPPTRAJ: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput. 2013;9(7):3084–3095. PubMed

Hollingsworth SA, Dror RO. Molecular dynamics simulation for all. Neuron. 2018;99(6):1129–1143. PubMed PMC

Santos LA, Prandi IG, Ramalho TC. Could quantum mechanical properties be reflected on classical molecular dynamics? The case of halogenated organic compounds of biological interest. Front Chem. 2019;7:848. PubMed PMC

Tavares CA, et al. Molecular dynamics-assisted interaction of vanadium complex–AMPK: from force field development to biological application for Alzheimer’s treatment. J Phys Chem B. 2023;127(2):495–504. PubMed

Hyperchem . Release 7.0 for Windows. Gainesville FL USA: Hypercube Inc.; 2001.

Pyper NC. Relativity and the periodic table. Phil Trans R Soc A. 2020;378(2180):20190305. PubMed

Sargsyan K, Grauffel C, Lim C. How molecular size impacts RMSD applications in molecular dynamics simulations. J Chem Theory Comput. 2017;13(4):1518–1524. PubMed

Del Río D, et al. Synthesis, molecular structure and properties of oxo-vanadium (IV) complexes containing the oxydiacetate ligand. Dalton Trans. 2003;9:1813–1820.

Sprenger K, Jaeger V, Pfaendtner J. The general AMBER force field (GAFF) can accurately predict thermodynamic and transport properties of many ionic liquids. J Phys Chem B. 2015;119(18):5882–5895. PubMed

Rabet S, Raabe G. Comparison of the GAFF, OPLSAA and CHARMM27 force field for the reproduction of the thermodynamics properties of furfural, 2-methylfuran, 2, 5-dimethylfuran and 5-hydroxymethylfurfural. Fluid Phase Equilib. 2022;554:113331.

Jójárt B, Martinek T. Performance of the general amber force field in modeling aqueous POPC membrane bilayers. J Comput Chem. 2007;28(12):2051–2058. PubMed

Del Río D, et al. Synthesis, antiapoptotic biological activity and structure of an oxo–vanadium (IV) complex with an OOO ligand donor set. Inorg Chem Commun. 2000;3(1):32–34.

Naqvi AAT, et al. Advancements in docking and molecular dynamics simulations towards ligand-receptor interactions and structure-function relationships. Curr Top Med Chem. 2018;18(20):1755–1768. PubMed

Alonso H, Bliznyuk AA, Gready JE. Combining docking and molecular dynamic simulations in drug design. Med Res Rev. 2006;26(5):531–568. PubMed

Kaleağasioğlu F, A DM, Berger MR. Multiple facets of autophagy and the emerging role of alkylphosphocholines as autophagy modulators. Front Pharmacol. 2020;11:547. PubMed PMC