Neuropilin-1 (NRP-1), a surface transmembrane glycoprotein, is one of the most important co-receptors of VEGF-A165 (vascular endothelial growth factor) responsible for pathological angiogenesis. In general, NRP-1 overexpression in cancer correlates with poor prognosis and more tumor aggressiveness. NRP-1 role in cancer has been mainly explained by mediating VEGF-A165-induced effects on tumor angiogenesis. NRP-1 was recently identified as a co-receptor and an independent gateway for SARS-CoV-2 through binding subunit S2 of Spike protein in the same way as VEGF-A165. Thus, NRP-1 is of particular value as a target for cancer therapy and other angiogenesis-dependent diseases as well as for SARS-CoV-2 antiviral intervention. Herein, The Super Natural II, the largest available database of natural products (~0.33 M), pre-filtered with drug-likeness criteria (absorption, distribution, metabolism and excretion/toxicity), was screened against NRP-1. NRP-1/VEGF-A165 interaction is one of protein-protein interfaces (PPIs) known to be challenging when approached in-silico. Thus, a PPI-suited multi-step virtual screening protocol, incorporating a derived pharmacophore with molecular docking and followed by MD (molecular dynamics) simulation, was designed. Two stages of pharmacophorically constrained molecular docking (standard and extra precisions), a mixed Torsional/Low-mode conformational search and MM-GBSA ΔG binding affinities calculation, resulted in the selection of 100 hits. These 100 hits were subjected to 20 ns MD simulation, that was extended to 100 ns for top hits (20) and followed by post-dynamics analysis (atomic ligand-protein contacts, RMSD, RMSF, MM-GBSA ΔG, Rg, SASA and H-bonds). Post-MD analysis showed that 19 small drug-like nonpeptide natural molecules, grouped in four chemical scaffolds (purine, thiazole, tetrahydropyrimidine and dihydroxyphenyl), well verified the derived pharmacophore and formed stable and compact complexes with NRP-1. The discovered molecules are promising and can serve as a base for further development of new NRP-1 inhibitors.

Plant cell cultures of Silybum marianum L. are studied under different classes of elicitors including heavy metal ions (Ag+), polysaccharides (yeast extract and chitosan), and plant response signaling compounds (salicylic acid) in order to enhance silybin production. Remarkably, all elicitors enhanced the accumulation of silybin compared to the control experiment, but the highest total silybin content was achieved in cell suspensions elicited with yeast extract at 0.5 μg.ml−1 producing a total silybin yield at 0.15 mg.g−1 cells dry weight after 2 days of elicitation for a total cell dry weight of 1.49 g. The lowest silybin accumulation belongs to chitosan treatment producing maximum silybin content and dry weight of 0.038 mg.g−1 DW and 1.19 g, respectively. These results are promising to establish a proof of concept using yeast extract as a viable elicitor option to produce silybin in tissue culture. Practical applications Optimization of elicitor‐induced cell culture production of secondary metabolites is important to develop a proof concept that can be easily scaled‐up and stand as an economically viable solution to meet the increasing demand for health and food supplements. In fact, the production of secondary metabolites from tissue cultures permits space and resource optimization, protects endangered endemic plants, and contributes to food/health security and sustainable development.