The identification of novel inhibitors of human angiotensin-converting enzyme 2 and main protease of Sars-Cov-2: A combination of in silico methods for treatment of COVID-19.

The angiotensin-converting enzyme 2 (ACE2) and main protease (MPro), are the putative drug candidates for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, we performed 3D-QSAR pharmacophore modeling and screened 1,264,479 ligands gathered from Pubchem and Zinc databases. Following the calculation of the ADMET properties, molecular docking was carried out. Moreover, the de novo ligand design was performed. MD simulation was then applied to survey the behavior of the ligand-protein complexes. Furthermore, MMPBSA has utilized to re-estimate the binding affinities. Then, a free energy landscape was used to find the most stable conformation of the complexes. Finally, the hybrid QM-MM method was carried out for the precise calculation of the energies. The Hypo1 pharmacophore model was selected as the best model. Our docking results indicate that the compounds ZINC12562757 and 112,260,215 were the best potential inhibitors of the ACE2 and MPro, respectively. Furthermore, the Evo_1 compound enjoys the highest docking energy among the designed de novo ligands. Results of RMSD, RMSF, H-bond, and DSSP analyses have demonstrated that the lead compounds preserve the stability of the complexes' conformation during the MD simulation. MMPBSA data confirmed the molecular docking results. The results of QM-MM showed that Evo_1 has a stronger potential for specific inhibition of MPro, as compared to the 112,260,215 compound.

Publisher Correction: Fatty acid synthase, a novel poor prognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fatty acid synthase, a novel poor prognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract.

Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL). To evaluate the impact of fatty acid synthase (FASN) on drug resistant ALL, bone marrow samples were collected from 65 pediatric ALLs, including 40 de novo and 25 relapsed patients. 22 non-cancer individuals were chosen as controls. Quantitative RT-PCR showed increased expression levels of FASN in drug resistant patients compared with the therapy responders. Single and combined treatment of malignant cells were analyzed using Annexin-V/PI double staining and MTT assays. Incubation of resistant primary cells with ginger showed simultaneous increased apoptosis rates and reduced FASN expression levels. Furthermore, docking studies demonstrated high affinity bindings between ginger derivatives and FASN thioesterase and ketosynthase domains, compared with their known inhibitors, fenofibrate and morin, respectively. Finally, combined treatment of in-house multidrug resistant T-ALL subline with ginger and dexamethasone induced drug sensitivity and down regulation of FASN expression, accordingly. To the best of our knowledge, this is the first study that introduces FASN upregulation as a poor prognostic factor for drug resistant childhood ALL. Moreover, it was revealed that FASN inhibition may be applied by ginger phytochemicals and overcome dexamethasone resistance, subsequently.