Peer Review #1 of "Steroidal glycoalkaloids from Solanum nigrum target cytoskeletal proteins: an in silico analysis (v0.1)"

Abstract

Background: Solanum nigrum (black nightshade; S. nigrum), a member of family Solanaceae, has been endowed with a heterogeneous array of secondary metabolites of which the steroidal glycoalkaloids (SGAs) and steroidal saponins (SS) have vast potential to serve as anticancer agents. Since there has been much controversy regarding safety of use of glycoalkaloids as anticancer agents, this area has remained more or less unexplored. Cytoskeletal proteins like actin play an important role in maintaining cell shape, synchronizing cell division, cell motility etc. and along with their accessory proteins may also serve as important therapeutic targets for potential anticancer candidates. In the present study, glycoalkaloids and saponins from S. nigrum were screened for their interaction and binding affinity to cytoskeletal proteins, using molecular docking. Methods:Bioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis were performed using softwares Molinspiration and Osiris Data Explorer respectively, to assess the feasibility of selected phytoconstituents as potential drug candidates. The results were compared with two standard reference drugs doxorubicin hydrochloride (anticancer) and tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA). Results: Docking analysis revealed that the binding affinities of the phytoconstituents towards the target cytoskeletal proteins decreased in the order coronin>villin>ezrin>vimentin>gelsolin>thymosin>cofilin.Glycoalkaloid solasonine displayed the greatest binding affinity towards the target proteins followed by alpha-solanine whereas amongst the saponins, nigrumnin-I showed maximum binding affinity. PASS Analysis of the selected phytoconstituents revealed 1 to 3 violations of Lipinski's parameters indicating the need for modification of their SAR for improvement of their bioactivity and bioavailability. Glycoalkaloids and saponins all had bioactivity scores between -5.0 and 0.0 with respect to various receptor proteins and target enzymes.Solanidine, solasodine and solamargine had positive values of druglikeness which indicated that these compounds have the potential for development into future anticancer drugs. Toxicity potential evaluation revealed that glycoalkaloids and saponins had no PeerJ reviewing PDF | (Manuscript to be reviewed toxicity, tumorigenicity or irritant effect(s). SAR analysis revealed that the number, type and location of sugar or the substitution of hydroxyl group on alkaloid backbone had an effect on the activity and that the presence of α-L-rhamnopyranose sugar at C-2 was critical for a compound to exhibit anticancer activity. Conclusion: The present study revealed some cytoskeletal target(s) for S. nigrum phytoconstituents by docking analysis that have not been previously reported and, thus, warrant further investigations both in vitro and in vivo. Manuscript to be reviewed 1 Running title: Molecular docking analysis of Solanum nigrum alkaloids to cytoskeletal proteins 2 Steroi...