No abstract

c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as "fourth generation inhibitors" constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein-ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers.

: The last generation of Coronavirus named COVID-19 is responsible for the recent worldwide outbreak. Concerning the widespread and quick predominance, there is a critical requirement for designing appropriate vaccines to surmount this grave problem. Correspondingly, in this revision, COVID-19 vaccines (which are being developed until March 29th, 2021) are classified into specific and non-specific categories. Specific vaccines comprise genetic-based vaccines (mRNA, DNA), vector-based, protein/recombinant protein vaccines, inactivated viruses, live-attenuated vaccines, and novel strategies including microneedle arrays (MNAs), and nanoparticles vaccines. Moreover, specific vaccines such as BCG, MRR, and a few other vaccines are considered Non-specific. What is more, according to the significance of Bioinformatic sciences in the cutting-edge vaccine design and rapid outbreak of COVID-19, herein, Bioinformatic principles including reverse vaccinology, epitopes prediction/selection and, their further applications in the design of vaccines are discussed. Last but not least, safety, challenges, advantages, and future prospects of COVID-19 vaccines are highlighted.

Background:The prominent hallmark of malignancies is the metastatic spread of cancer cells. Recent studies have reported that the nature of invasive cells could be changed after this phenomenon, causing chemotherapy resistance. It has been demonstrated that the up-regulated expression of matrix metalloproteinase (MMP) 2/MMP-9, as a metastasis biomarker, can fortify the metastatic potential of leukemia. Furthermore, investigations have confirmed the inhibitory effect of cannabinoid and endocannabinoid on the proliferation of cancer cells in vitro and in vivo. Methods:In the present study, the inhibitory effect of WIN 55212-2 (a CB1/CB2 receptor agonist) and AM251 (a selective CB1 receptor antagonist) on K562 cells, as a chronic myelogenous leukemia (CML) model, was evaluated using MTT and invasion assay. Expressions of MMP-2 and MMP-9 were then assessed by Western blot analysis.Results:The data obtained from MTT assay showed that WIN 55212-2 could attenuate cell proliferation; however, AM251 was less effective in this regard. Our results showed that WIN 55212-2 considerably reduced cancer cell invasiveness, while AM251 exhibited a converse effect. Moreover, CB1 activation resulted in decreased expression of MMP-2 and MMP-9. Conclusion:Our findings clarifies that CB1 receptors are responsible for anti-invasive effects in the K562 cell line.

IntroductionBreast cancer is the primary cause of death in malignancies among females (Regulski et al., 2016). It is suggested that a major population of breast tumor was incapable of further growth but only a minute fraction was able to seed new cancers, called cancer stem cells (CSCs) (Al-Hajj et al., 2003). During recent years, studies have identified CSCs as the subpopulation of tumor cells with a unique capacity for self-renewal and the ability to give rise to a heterogeneous population of cancer cells to form tumors. Genomic instability via several gene mutations has been reported to form CSCs from normal stem cells, progenitor cells, or differentiated cells. Cancer development could be due to the fact that CSCs are associated with tumor initiation, progression, and metastasis as well as treatment resistance. Thus, CSCs have been discovered to be a suitable therapeutic target for prevention and treatment of cancer (Soltanian and Matin, 2011;Sotiropoulou et al., 2014). Breast CSCs are multiple, distinct, and nonoverlapping populations coexisting within the tumor mass (Wright et al., 2008). In 2003, breast CSCs with CD44 + /CD24 -/low / ESA + cell surface markers were isolated for the first time by Al-Hajj et al. (2003). Additionally, ALDH1, which belongs to the aldehyde dehydrogenase family, is a putative CSC marker, including breast cancer. To date, several breast cancer stem cell markers have been proposed (CD133, CD29, and CD49f), of which CD44 + /CD24 -/low and ALDH1 are used exclusively to identify these highly tumorigenic cells (Carrasco et al., 2014).The cyclooxygenase enzyme, which mediates prostaglandin production, consists of three isoforms, COX-1, COX-2, and COX-3. COX-1, a house-keeping enzyme, has a crucial role for internal homeostasis. Conversely, COX-2 is undetectable in normal tissues while it is inducible in the setting of neoplasia and inflammation (Regulski et al., 2016). COX-2 upregulation by modulating various signaling pathways can enhance production of prostaglandins, which promote tumor growth, invasion, angiogenesis, and apoptosis resistance. Recent studies have also attributed the overexpression of COX-2 to breast cancer stem-like cell (CSC-LCs) properties and cancer development (Jeong et al., 2010;Singh et al., 2011).