## 3 Results
### Natural Molecules  
Historically, natural products, which contain a wide range of compounds for drug discovery, have been considered in multiple clinical trials, especially as anticancer and antimicrobial agents [28]. The advantage of natural products with respect to synthetic compounds is that they are also metabolites. Therefore, they are biologically active and can also be substrates for transporter systems [28]. Table 2 shows the works in the last five years that have implemented in silico and in vitro models for drug discovery using natural ligands as drugs for metastatic BC. Hypercholesterolem has been reported to play a role in the progression of BC and resistance to hormonal therapy. High low-density lipoprotein (LDL) levels, primarily caused by familial hypercholesterolemia, are also one of the risk factors of the initiation and promotion of BC [29]. Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptors (avoiding binding with LDL) and regulates the cholesterol metabolism, targeting the receptor for lysosomal degradation and thus leading to the degradation of LDL. Pseurotin A (PS) is a microbial secondary metabolite originally isolated from the fungal culture of _Pseuderuotin ocalis_ in 1976 [30]. PS shows different biological activities, including the inhibition of the fungal chitin synthase [31], the activation of cell differentiation [32], and apomorphine antagonist activity [33]. [PERSON] et al. showed that PS reduces PCSK9 secretion, suggesting its potential as a drug [34]. In particular, they performed predictive molecular modeling to evaluate the binding of PS to PCSK9 (PDB ID: 4 NE9, 4 NMX, and 3 GCW). Docking analysis has revealed that PS is able to successfully bind to the PCSK9 domain, thereby disrupting PCSK9-LDL receptor interactions. Furthermore, this finding has been validated in vitro by surface plasmon resonance, confirming the capacity of PS to interfere with the PCSK9-LDL complex at their binding interface. \begin{table}
\begin{tabular}{c c c c c c c c c} \hline
**Drug** & **Target** & **In Silico** & **In Vitro** & **In Vivo** & **Clinical Trials** & **Original Use** & **Ref. ** \\ \hline \hline \multirow{2}{*}{Repinites} & \multirow{2}{*}{anomalise enzyme (PDB 1 ID: 3 EGM)} & \multirow{2}{*}{Docking studies} & \multirow{2}{*}{MTT 2 assay} & - & - & \multirow{2}{*}{antiparkinson} & [19] \\  & & & & & & & \\ \hline
15 small molecular compounds & \multirow{2}{*}{CCL18 (PDB ID: 4 MBF)} & \multirow{2}{*}{Docking studies} & Cell viability, Boyden chamber, albumene assay & \multirow{2}{*}{Tumor xenografts} & - & \multirow{2}{*}{CCL18 antagonist} & [20] \\ \hline \multirow{2}{*}{Topoisomerase inhibitor} & \multirow{2}{*}{TRAL-DRS (PDB ID: A890)} & \multirow{2}{*}{Docking, mutational and dynamic studies} & \multirow{2}{*}{MTT assay, FACS 3} & \multirow{2}{*}{Tumor xenografts} & \multirow{2}{*}{NCT0004 906} & against a wide range of \\  & & & & & & & \\ \hline \multirow{2}{*}{Thiceineine} & \multirow{2}{*}{human serum albumin (HSA)} & \multirow{2}{*}{Docking, mutational and fluorescence microscopic} & - & - & against bacteria, viruses & [24] \\  & & & & & & and yeasts & \\ \hline \multirow{8}{*}{2,4-fluoroeth  
In an another study, the interactions of atranorin (ATR), a metabolite of many lichens, with the target proteins that are overexpressed in BC, such as AKT, BCL-2, BAX, BCL-W, and BCL-XL, were studied with docking and in vitro analyses [35]. Commonly, ATR is metabolite present in numerous lichens such as _Stereocaulon caspitorim_, _Everniastrum vezans_, _Parmatrema_ species, and others [35]. The complex formed by ATR and AKT shows a better binding energy, but interacting residues show minor affinities to inhibiting the overexpression of BC biomarkers. Interestingly, previous studies have reported the activation of AKT in drug resistance [36] and in vitro studies have been performed on MDA-MB-231 and MCF-7. The inhibitory activity of ATR has been tested with MTT assays, showing a downregulation of oncoprotein.