## 4 Computer-Aided Molecular Design (CAMD) of Coumarins for Potential Plant Protection Application
### QSAR  
There is a limited number of published QSAR studies about coumarins as agents against phytopathogenic fungi. [PERSON] et al. [32] performed simple structure-activity relationship (SAR) analyses of the antifungal activity of 35 coumarin derivatives against _S. sclerotorum_ and _B. cinerea_, without quantitative evaluation. SAR study revealed that the coumarins with esters at their C-5 position showed higher antifungal activities than the  
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corresponding compound with a hydroxyl group at the same position. [PERSON] et al. [133] evaluated the acaricidal potency of thirty phenolic ether derivatives of scopoletin against female adults of _Tetranychus cinnabarinus_, the most economically important arthropod pest. They derived a QSAR model with five descriptors calculated by the Dragon program (three GETAWAY descriptors; one drug-like indice; one 2D autocorrelation indice; and one topological indice [134]. The published model has satisfactory fitting parameters (high squared correlation coefficient, \(R^{2}_{\text{train}}=0.875\)), with a high internal predictivity for chemicals in the data set. However, its external predictivity was unreliable considering the low \(R^{2}_{\text{ext}}\) (0.583).  
A predictive MLR QSAR model [35] was obtained for the antifungal activity against _M. phaseulina_ (\(R^{2}_{\text{train}}=0.78\); \(R^{2}_{\text{ext}}=0.67\); \(Q^{2}_{\text{loo}}=0.67\)) for 31 of coumarin derivatives:  
\[\log\%\text{inhibition}=1.82+5.55\,JGI6-0.72\,Mor28v-0.05\,L2e \tag{1}\]  
where molecular descriptor _JGI6_ belongs to the topological charge indices, _Mor28v_ is 3D-MoRSE (Molecular Representation of Structures based on Electronic diffraction), and _L2e_ is WHIM (Weighted Holistic Invariant Molecular). According to the obtained QSAR model, multiple electron-withdrawal groups, especially at position C-3, promote, while benzoyl groups and Br atoms at C-8 reduce inhibition. Although the predictivity of the QSAR model for antifungal activity against S. sclerootinrum failed, internal validation confirmed the model's stability. This makes it relevant for explaining the relation of the structure to observed activity. The model indicates that the hydrophobic benzoyl group at the pyrone ring, and -Br, -OH, -OCH\({}_{3}\), at the benzene ring, may increase inhibition of _S. sclerootinrum_.  
[PERSON] et al. [44] developed linear and nonlinear QSAR models by three machine learning methods, GA-MLR, LS-SVM, and PPR, for predicting the fungicidal activities of 100 thiazoline derivatives against rice blast caused by _Magnaporthe grisea_. The obtained models demonstrated strong correlations between the 3D and conformational structures of the molecules and the fungicidal activities of these compounds.  
[PERSON] et al. [135] have generated a QSAR model for 25 coumarin derivatives, which exhibited acaricidal activities against _Tetranychus cinnabarinus_ Bois. using stepwise regression analysis method (\(R^{2}=0.967\) and \(F=155.176\)). Although the model performed well in fitting, internal and external validation was not conducted, so it cannot be characterized as predictive.  
[PERSON] et al. [34] developed 3D-QSAR models for antifungal activities against _Valsa mali_ of coumarin derivatives using the CoMFA/CoMSIA method. Derived CoMFA and CoMSIA models (\(R^{2}=0.918\) and \(0.949\), respectively) revealed small, electron-withdrawing and hydrophilic groups on C-3 and C-8 enhanced antifungal activity.  
CoMFA and CoMSIA analysis was performed on the scopoletin and coumarine derivates to study the relationship their structure and inhibition of _Tetranychus cinnabarinus_ plasma membrane Ca\({}^{2+}\)-ATPase 1 gene (TcPMCA1), which is responsible for the development of various life stages of carmine spider mite _T. cinnabarinus_. The results of 3D-QSAR models indicate that substitutions at C-3, C-6, and C-7 positions of coumarins are important for their acaricidal activity [136].