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Jasmonates and related compounds have been highlighted recently in the field of plant physiology and plant molecular biology due to their significant regulatory roles in the signaling pathway for the diverse aspects of plant development and survival. Though a considerable amount of studies concerning their biological effects in different plants have been widely reported, the molecular details of the signaling mechanism are still poorly understood. This review sheds new light on the structural requirements for the bioactivity/property of jasmonic acid derivatives in current computational perspective, which differs from previous research that mainly focus on their biological evaluation, gene and metabolic regulation and the enzymes in their biosynthesis. The computational results may contribute to further understanding the mechanism of drug-receptor interactions in their signaling pathway and designing novel plant growth regulators as high effective ecological pesticides.
Over the past decades, a tremendous amount of studies has led to new insights into the growth, development and survival of various plants in different places. It has been found that plants have built up highly effective and complex octadecanoid signaling pathways known as “signal transduction”.1,2 If rapid and effective defense responses are triggered by biotic and abiotic stresses, the defensive signals will surely be transduced and amplified via a number of pre-existing complex signaling pathways, activating systemic acquired resistance (SAR).3,4 Jasmonates and related compounds, a family of signaling mediators, are locally and systemically involved in these actions as regulators controlling the expression of many genes that encode defensive proteins,5,6 thus have attracted much interest lately.7–11 Therefore, plants can equilibrate the exoteric stresses as well as coordinate the developmental processes by themselves in the life cycle.
Since the initial discovery of bioactivity jasmonic acid and its methyl ester respectively in 1962 and 1971,12 jasmonates are a growing class of signaling molecules and plant hormones which are derived from polyunsaturated fatty acids via the octadecanoid pathway and characterized by a pentacyclic ring structure. Jasmonates and related compounds, including amino acid conjugates of jasmonic acid, are ubiquitous in the plant kingdom.13 Considerable studies have shown that they have various physiological activity in response to environmental stresses and biotic challenges and many aspects of plant developmental processes.14–21 Based on their significance to plants, they have been highlighted in the field of plant physiology and plant molecular biology recently.19 Though their biological effects, gene and metabolic regulation and the enzymes in their biosynthesis have been studied for years, the molecular details of the signaling mechanism at biochemical level are still poorly understood.10,11,22
This review presents a new way to study the possible signaling mechanism and the substitutional requirements for the bioactivity/property of jasmonates and related compounds in plants. Quantitative structure-activity relationship (QSAR) analysis pioneered by Hansch et al.23 helps to quantitatively correlate the activity or properties of compounds in series with their measured or computed physiochemical properties and has proved to be an useful approach in modern drug discovery.24,25 They rationalize the drug synthesis and provide an insight into the mechanism of drug-receptor interactions. Until now, there are few systematical structure-activity studies about them available,26–31 indicating that C-1, C-2 and C-3 positions of jasmonic acid are important for their various activity. But these previous studies were just performed in the non-quantitative traditional ways that different substituents changed in these positions vary their activity. Thus the quantitative results obtained in the computational perspective can be of great help.
Until now, there are fewer research papers reporting the accurate numeric activity of jasmonates and related compounds, such as references 28 and 29. Without the accurate activity data, it is difficult to perform computer-assisted drug design (CADD) methods, which may explain why many experts focus on the synthesis and biological evaluation of the analogs of jasmonic acid and finally discuss the various substituents in cyclopentanone of jasmonic acid influencing the activity in the traditional ways.
Currently, quantitative structure-activity relationship (QSAR) method was first applied to 18 jasmonates and related compounds32 that were reported by Blechert et al.28 quantitatively studying the relationships between chemical structure and their biological activity in barley and tomato bioassay. Statistically significant 2D-QSAR models (r2 > 0.880 and cross-validated r2 > 0.820) were developed by genetic function approximation (GFA)33 in Cerius2 software (Version 4.10), indicating that the biological activity (pKi-1) was principally influenced by thermodynamic descriptors (Atype_C_60 and Atype_C_38), electronic descriptor (Dipole-mag) and spatial descriptor (Jurs-RPSA) and the biological activity (pKi-2) was principally governed by electronic descriptor (HOMO), structural descriptor (Hond Acceptor) and thermodynamic descriptor (Atype_C_16). Here, Ki-1 (%) and Ki-2 (%) represented relative chlorophyll loss ratio (%) in barley and tomato senescence bioassays, respectively, which had already been expressed as log (1/Ki). The detailed meaning of descriptors can be seen in the paper.32 Besides, molecular field analysis (MFA)34 coupled with genetic partial least squares (G/PLS) method35,36 were also employed to derive 3D-QSAR models, investigating the substitutional requirements for the favorable receptor-drug interaction, and quantitatively indicating the important regions of molecules for their activity.32 MFA attempts to postulate and represent the essential features of a receptor site from the aligned common features of the molecules that bind to it, which is especially effective for the analysis of the data sets with available activity data but unknown receptor site structure.36 At present, the receptors that jasmonates and related compounds bind to are still unclear yet. Thus, MFA-G/PLS study of these compounds will contribute to further understanding the structural requirements for the bioactivity of jasmonates and related compounds. The 3D-QSAR models showed that electrostatic interactions are crucial to pKi-1 and moderate steric interactions are favored to pKi-2, indicating tiny transformation in the meso-position and para-position of cyclopentanone may greatly change the biological activity. These results are also approximately in accordance with the previous studies.26–31 Therefore, combination of 2D-QSAR and 3D-QSAR models can be of great help for experts to better predict the possible activity of compounds in series and design novel analogs of jasmonic acid with high biological activity.
Lipophilicity, usually expressed as the logarithm of n-octanol/water partition coefficient (logP), plays an important role in ligand-receptor interactions,37 and is one of the major properties that influence the transport, absorption and distribution of chemicals in biological systems.38 Recently, how plants manage events has been suggested to be related to jasmonates' natural workings in the form of direct or indirect penetration of their cells.9 Thus, logP is essential for the signaling abilities of jasmonates and related compounds, whether they are exogenous or endogenous.
Lately, quantitative structure-property relationship (QSPR) was first performed on the 59 reported amino acid conjugates of jasmonic acid with lipophilicity in form of log P calculated in Cerius2 software (Version 4.10).19 Statistically significant 2D-QSPR model (r2 = 0.990 and cross-validated r2 = 0.987) developed by GFA method showed that the calculated logP of amino acid conjugates of jasmonic acid was influenced by structural descriptors (Hond Donor and Density), electronic descriptor (Apol) and E-State-keys (S_ssO), which could be approved by the usage of descriptors during QSPR models generation. The detailed meaning of descriptors can be seen in the paper.19 In addition, the results of the 2D-QSPR model were further compared with 3D-QSPR model. 3D-QSAR model (r2 = 0.922 and cross-validated r2 = 0.841) with good stability and predictability was generated by MFA-GFA method to further study the structural requirements for the logP of these compounds in series, indicating bulky substituents at C7 position were unfavored to the logP and both steric and electrostatic substituents at C3 position were important to logP. The logP values of test set molecules were also well predicted, thus the derived QSPR models were significant and the important regions and the molecular structural parameters were found for these series. Another paper39 (words in Chinese) also presented the QSPR study on the physiochemical properties (AlogP, logP and AlogP98) of 30 jasmonates and related derivatives, and the results were interesting.
Jasmonates and related compounds are essential for plants' survival in nature.40 Along with the application of modern techniques and methods, more and more analogs of jasmonic acid will be discovered and exogenous applied in the plants to further study their roles in regulate plants' developmental processes and defensive responses against exoteric attack. For these compounds are universal in plants, they have the effects of ecological pesticides.32 The biological activity evaluation of them will be surely further investigated in the coming years, not restricted in a few biological systems, which will affirmatively interpret the data to fully understand the perception of mechanism of them in various plants.
Due to the successful application of CADD methods to modern drug discovery, it makes possible that quantitative microstructure required for activity of jasmonates and related compounds will be explored. At present, only three papers ( refs. 19, 32 and 39) reported the study of them using computational methods. Thus, there is an urgent need to further study these compounds in computational perspective, quickening the design of analogs of jasmonic acid in series with high biological activity. Besides the 2D/3D-QSAR/QSPR methods, the following methods may be also of great help. Quantum chemistry and molecular mechanics can be employed to study the optimum conformations of compounds with lowest energy that are supposed to be existing steadily in plants, and the relationships between the activity and charge distribution, bond length, angle and molecular occupied or virtual orbital can be studied for further molecular design. Furthermore, pharmacophore can also be used to explore specific, three dimensional maps of biological properties common to all active conformations of a set of analogs of jasmonic acid that exhibit particular activity, showing the specific molecular regions that interact with surrounding hydrophobic, aromatic, a hydrogen bond acceptor and so on in plants. This method can be widely used not only in drug identification and design studies, but also in lead optimization for potency and reduction of toxicity. Quantitative structure-retention relationship (QSRR) method41,42 can also be employed to predict the chromatographic retention indexes of unknown analogs of jasmonic acid, which can help experts to estimate the compounds in series found accidentally. Through the various computational studies on the jasmonates and related compounds, the mechanism of drug-receptor interactions in their signaling pathway will be well understood and novel analogs of jasmonic acid with high biological activity will be designed fleetly.
This work is supported by the National Natural Science Foundation of China (No. 30500339), the Natural Science Foundation Program of Zhejiang Province (No. Y407308) and the merit based research project for scholars returning from abroad.
Previously published online: www.landesbioscience.com/journals/psb/article/9717