The physicochemical properties and tyrosinase inhibitory activity of ectoine and its analogues: A theoretical study

https://doi.org/10.1016/j.comptc.2018.03.003Get rights and content

Highlights

  • Ectoine and its derivatives have same pharmacophore and thermodynamic properties.

  • All diversities are effective inhibitors on tyrosinase and also are more active than Ectoin.

  • Ectoine's derivatives are drug-like compound in skin protection.

Abstract

Protonation, deprotonation, and proton transfer were considered in ectoine (ECT) and some of its derivatives in the gas phase and solution media by the quantum mechanical calculations. The results of present study help to understand the activity of mentioned compounds as osmolytes, which are also important in water activity and osmotic pressure within a cell. Proton diffuses through the water solvent, covers the distance between the acidic and basic groups, and leads to the protonation of basic group. The deprotonation of NH group is often easier than COOH, because of intramolecular H-bond interactions in the anionic forms. The protonation of N atom is easier than the deprotonation of COOH and NH groups in all compounds with respect to the energy data, results of atoms in molecules (AIM), and molecular electrostatic potential (MEP) analyses. The proton transfer from NH to N is favorable in solution media, acidic and basic environments which is in agreement with the high tendency of NH group and N atom in deprotonation and protonation, respectively. Results indicate that protonation, deprotonation, and proton transfer are almost the same in all compounds and lead to the same biological activities. In addition, the inhibitory activity of compounds on tyrosinase enzyme was studied using the results of molecular docking. The proper orientation of PO3H2 group in the binding pocket causes suitable interactions with HIS244, GLU256, and ASN260 amino acids. Thus, it seems that the highest inhibitory activity corresponds to the compound with the –CH2-PO3H2 substituent.

Introduction

The solutes with high osmotic coefficients have been introduced as powerful anti-stress agents [1]. A group of non-toxic solutes with low molecular weights, which are known as “compatible solutes”, protect biomolecules through reducing harmful effects such as radiation, freezing, drying, radicals, and high temperatures [2], [3], [4].

One of the most-studied compatible solutes with small molecules that helps organisms to stay alive in extreme osmotic stress is 1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid, which is called ectoine (ECT). It is a natural zwitterionic agent that is found in high concentrations in Ectothiorhodospira Halophilic microorganisms [5], [6]. ECT has been identified in a wide range of gram-negative and gram-positive bacteria such as α- and γ-Proteobacteria, Actinobacteridae, β-, δ-, and ε-Proteobacteria, Firmicutes, and one Plantomycete [7]. It is usually synthesized at industrial scale by a new biotechnological process called “bacterial milking” [8].

On the other hand, ECT can be used as energy, carbon or nitrogen sources [9], [10]. Another role of ECT is macromolecule protection, including DNA, enzyme, and protein protection [11]. For example, decreasing the melting point of double stranded DNA increases the catalytic capacity and thermal stability of phytase and DNA polymerases at high temperature, respectively [12]. ECT is a cell protectant, which improves cell growth and glucose utilization in ethanologenic bacterium Zymomonas mobilis or increases the nitrogen supply to leaves, which makes higher the rate of photosynthesis in tobacco plants [13], [14]. ECT intervenes with signaling pathways such as mitogen-activated protein kinase and cytokine to reduce the inflammatory response [15], [16].

Also, ECT is active in skin protection [17]. For example, it protects the skin from dehydration by stabilizing the membranes against the damaging effect of surfactants and the stress factors [18], [19]. In addition, it affects the UVA-induced cell damage by a singlet oxygen-mediated mechanism which prevents the photocarcinogenesis, photodermatoses, and photoageing [20]. It might protect skin from oxidative damage using its anti-aging properties [21]. These abilities make ECT a high-quality skin care product because of its long-term moisturizing efficiency [22]. A recent study showed that ECT is an effective and non-toxic whitening agent which reduces tyrosinase activity and has inhibitory effects on the expressions of melanogenesis-related genes [23].

In this study, electronic structure, some geometrical features, and thermodynamic properties of ECT and its derivatives (see Scheme 1) are investigated using the quantum mechanical calculations. In addition, their inhibitory effects on tyrosinase activity are estimated to introduce the best agent for prevention of cells from melanogenesis [23]. ECT derivatives with pharmacological potential including hydroxyectoine (HYEC) have an additional hydroxyl group which adds another chiral center to the molecule and makes it a biotechnological alternative [24]. It improves the thermo-resistance property of proteins and cells, where has also a greater stabilization capacity as compared to ECT [25]. Additional methylene group inserted into the ring in homoectoine (HOEC) does not cause any change in the density behavior of system [1]. It can be supplemented in ECT polymerase chain reactions (PCRs), which enhances the efficiency of those reactions with GC-rich templates and also improves the primer extension or sequencing methods [26]. 2-methyl-6-phosphonomethyl-1,4,5,6-tetrahydro-pyrimidine-4-carboxylic acid (PMEC) and 2-methyl-6-(3-phosphono-propyl)-1,4,5,6-tetrahydro-pyrimidine-4-carboxylic acid (PPEC) are analogues of cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid (CGS 19755) which are useful antagonists of the N-methyl-d-aspartate receptor (NMDA) [27]. A phosphonomethyl or phosphonopropil group is replaced in ring as compared to ECT in the compounds PMEC and PPEC, respectively. The most important geometrical parameters and the atom labels of compounds are shown in Fig. 1.

Section snippets

Methods

The geometry optimizations were carried out at the M06-2X/6-311++G(d,p) level of theory [28] in the gas phase and solution media which the later were performed in implicit solvation according to the polarizable continuum model (PCM) using the GAUSSIAN09 program package [29]. The vibrational frequency calculations were also performed at the same level to ensure that the structures correspond to local minima and to calculate the Gibbs free energies. The topological properties of the electronic

Results and discussion

To investigate some structure related molecular properties of ECT and its derivatives the Gibbs free energy (ΔG) values were calculated in the gas phase and solution media in the anionic and cationic forms and reported in Table 1. The electron charge densities (ρ values) calculated at the H-bond critical points (HBCPs) between the COOH group and N atoms are gathered in Table 2. Anionic forms are obtained by removing H+ from the COOH or NH group. The ΔG values for the following reaction in the

Conclusions

The ΔG values calculated at the M06-2X/6-311++G(d,p) level in the gas phase and aqueous solution demonstrate that the acidity of NH group is higher than COOH group among the ECT and its derivatives with the exception of HOEC, where no intramolecular hydrogen bond interaction exists between the COsingle bondH group and the N atom in HOEC.

The ΔG values of protonation are in the range of −213 to −225 kcal mol−1 in the gas phase and −159 to −163.85 in the solution media which occur easier than deprotonation.

Acknowledgment

We thank the University of Sistan & Baluchestan for financial supports and Computational Quantum Chemistry Laboratory for computational facilities.

References (54)

  • C.F. Bigge et al.

    Synthesis of 6-phosphonoalkyl tetrahydro-4-pyrimidine-carboxylic acids as NMDA receptor antagonists

    Tetrahedron Lett.

    (1991)
  • Y. Wang et al.

    Inhibitory effect of morin on tyrosinase: insights from spectroscopic and molecular docking studies

    Food Chem.

    (2014)
  • P. Babkin et al.

    Antipsychotics inhibit glucose transport: determination of olanzapine binding site in Staphylococcus epidermidis glucose/H+ symporter

    FEBS Open Bio.

    (2015)
  • K.F. Debbabi et al.

    Synthesis and molecular docking against dihydrofolate reductase of novel pyridin-N-ethyl-N-methylbenzenesulfonamides as efficient anticancer and antimicrobial agents

    J. Mol. Struct.

    (2017)
  • W. Humphrey et al.

    VMD: visual molecular dynamics

    J. Mol. Graph.

    (1996)
  • Y. Zeng et al.

    Estimation of pKa values for carboxylic acids, alcohols, phenols and amines using changes in the relative Gibbs free energy

    Fluid Phase Equilibria

    (2012)
  • F. Salmannejad et al.

    Ectoine and hydroxyectoine inhibit thermal-induced aggregation and increase thermostability of recombinant human interferon Alfa2b

    Eur. J. Pharm. Sci.

    (2017)
  • L. Xu et al.

    Evaluation of nucleotide C-BrctdotO-P contacts from ONIOM calculations: theoretical insight into halogen bonding in nucleic acids

    Chem. Phys. Lett.

    (2011)
  • G. Lentzen et al.

    Extremolytes: natural compounds from extremophiles for versatile applications

    Appl. Microbiol. Biotechnol.

    (2006)
  • I. Yu et al.

    Microscopic understanding of preferential exclusion of compatible solute ectoine: direct interaction and hydration alteration

    J. Phys. Chem. B

    (2007)
  • K. Lippert et al.

    Enzyme stabilization be ectoine-type compatible solutes: protection against heating, freezing and drying

    Appl. Microbiol. Biotechnol.

    (1992)
  • H. Abdel-Aziz et al.

    Bacteria-derived compatible solutes ectoine and 5 α –hydroxyectoine act as intestinal barrier stabilizers to ameliorate experimental inflammatory bowel disease

    J. Nat. Prod.

    (2015)
  • E.S. Schweikhard et al.

    Structure and function of the universal stress protein TeaD and its role in regulating the ectoine transporter TeaABC of Halomonas elongata DSM 2581 T†

    Biochemistry

    (2010)
  • M.W. Vetting et al.

    Experimental strategies for functional annotation and metabolism discovery: targeted screening of solute binding proteins and unbiased panning of metabolomes

    Biochemistry

    (2015)
  • C. Vargas et al.

    Ectoines as compatible solutes and carbon and energy sources for the halophilic bacterium Chromohalobacter salexigens

    J. Appl. Microbiol.

    (2006)
  • L. Zhanga et al.

    Promoting effect of compatible solute ectoine on the ethanol fermentation by Zymomonas mobilis CICC10232

    Proc. Biochem.

    (2008)
  • R.E.A. Moghaieb et al.

    Characterization of salt tolerance in ectoine-transformed tobacco plants (Nicotiana tabaccum): photosynthesis, osmotic adjustment, and nitrogen partitioning

    Plant. Cell. Environ.

    (2006)
  • Cited by (5)

    View full text