Current Computer-Aided Drug Design

Prospects of Wedelolactone as a Chemotherapeutic Agent in Gynecological Cancers; Clue From its In Vitro and In Silico Investigation

Background:Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models.Objective:The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study.Methods:Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors.Results and Discussion:The IC50 value of WDL was 25.77 ± 4.82 μM and 33.64 ± 1.45 μM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB.Conclusion:We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

Methodological Verification-based Screening of the Representative Ingredients for Traditional Chinese Medicine: Taking Astragalus as an Example for Interfering with Cervical Cancer

Background:The screening of effective ingredients is the bridge between the research of efficacy and the mechanism of traditional Chinese medicine. Although promising virtual screening has emerged as an attractive alternative, an ideal strategy is still urgently required due to the characteristics of multi-ingredients and multi-targets of traditional Chinese medicine.Objective:The aim of the study was to develop a methodological verification-based novel screening strategy capable of comprehensively assessing the ability of compounds to perturb disease networks, thereby identifying representative ingredients of traditional Chinese medicine interventions in complex diseases.Methods:In this article, we take astragalus interfering with cervical cancer as an example. First, a multifunctional clustering disease network model was constructed; second, the several drugs and their decoys were used for molecular docking with disease network clusters for methodological verification and determining the best scoring criteria. Third, the representative ingredients of astragalus were screened according to the best scoring criteria. Finally, the effects of the representative ingredients on cervical cancer SiHa cells were evaluated by CCK-8 assay, flow cytometry, and western blot analysis.Results:Three representative ingredients of astragalus were betulinic acid, hederagenin and methylnissolin, which perturbed the apoptosis, stabilization of p53, and G1/S transition cluster as a whole, respectively. CCK-8 assay showed that the IC50 value of betulinic acid, hederagenin and methylnissolin at 48 h was 28.84, 101.90, and 187.40 μM, respectively. Flow cytometry showed that these three representative ingredients could significantly induce early apoptosis and cell cycle arrest. Western blot analysis showed that betulinic acid treatment significantly increased p53 expression, while hederagenin and methylnissolin did not.Conclusions:This study has provided new ideas for the screening of effective ingredients in traditional Chinese medicine, and established a foundation for elucidating the overall mechanism of action of traditional Chinese medicine

Methylaervine as Potential Lead Compound Against Cervical Carcinoma: Pharmacologic Mechanism Prediction based on Network Pharmacology

Background: The discovery of therapeutic anticancer agents based on natural products is one of the current research focuses. Network pharmacology will broaden our understanding of drug actions by bioinformatics analysis. Objective: To explore the potential and provide scientific evidence for methylaervine as a lead compound against cervical carcinoma. Methods: Methylaervine was synthesized, and its activity against four cancer cell lines was evaluated by MTT assay. Pharmacokinetic properties were obtained by in silico approaches, and the pharmacologic mechanism was predicted by network pharmacology. Then we validated and investigated our predictions of candidate targets using a molecular docking study. Results: Methylaervine was synthesized with a total yield of 54.9%, which displayed activity against HeLa (IC50 = 14.8 μM) with good predicted pharmacokinetic properties, thus it was considered a potential lead compound. The network pharmacology study indicated that methylaervine could act against cervical carcinoma by regulating the function of multiple pivotal targets, such as CTNNB1, PTPRJ, RPA1, and TJP1, mainly covering cell growth, cell motility, and cell proliferation. Moreover, docking analysis showed that hydrogen bonds and hydrophobic interactions were the main forms of interactions. Conclusion: This work would provide new insight into the design of anti-cervical carcinoma drugs based on methylaervine.