Current Computer - Aided Drug Design - Volume 18, Issue 4, 2022

Background: Hydrazide-hydrazone-based compounds are reported for their wider pharmacological potentials. Methods: In the present work, we synthesized 10 new Schiff-based-aryl-carbohydrazide (3a-3e) and (4a-4e) analogues and characterized further using standard spectroscopic techniques including NMR, mass and FT-IR. Moreover, all synthesized compounds were subjected to in vitro anti-TB, anti-microbial, antioxidant and anti-MCF-7 cell line studies. Results: Our results suggested that compounds have strong potencies against studied microbial species (such as 3a, 3b and 3c, (anti-TB activity: MIC value of 1.6 μg/mL; 3c:80.23 % inhibition at 200 μg/mL against MCF-7). Synthesized compounds (3a-3e) and (4a-4e) were also retained with higher docking scores than standards like ciprofloxacin; when studied for their molecular docking analysis against common anti-bacterial (pdb id:1d7u; 3a: -4.909 kcal/mol), common anti-fungal (pdb id:1ai9; 3b: -6.122 kcal/mol) and enoyl acyl reductase enzyme (pdb id:2x22; 3c: docking score: -4.194 kcal/mol)) targets. Conclusion: Thus, considering promising results for Schiff-based-aryl-carbohydrazides, these compounds may emerge as a new class for developing potent anti-microbial agents in the near future.

Background: Danggui Shaoyao San (DSS) is a well-known herbal formula, which has been widely used in the treatment of non-alcoholic fatty liver disease (NAFLD). However, the potential mechanisms of DSS for NAFLD remain unknown. Objective: Our study aims to explore the active components and potential molecular mechanisms of DSS for the treatment of NAFLD. Methods: In this study, network pharmacology and molecular docking were performed to predict the active ingredients, potential targets and molecular mechanisms of DSS for the treatment of NAFLD. Results: The 28 active components and 27 potential targets of DSS associated with NAFLD were identified, and five components most closely associated with NAFLD were beta-sitosterol, kaempferol, hederagenin, 3β-acetoxyatractylone, and sitosterol. DSS was involved in regulating pathways in cancer, AGE-RAGE signalling pathway in diabetic complications, IL-17 signalling pathway, NAFLD, hepatitis B, apoptosis, and hepatitis C. Additionally, IL-6, Caspase 3, RELA, PTGS2, and JUN might be the potential targets of DSS for NAFLD treatment. In addition, the results of molecular docking indicated that kaempferol and beta-sitosterol compounds could bind to the important targets. Conclusion: Our study systematically investigated the potential molecular mechanism of DSS for the treatment of NAFLD, which would potentially provide a new clinical approach for NAFLD.

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. The multifactorial etiology of AD has led to the design of multitarget directed ligands (MTDL) for AD. Tacrine an acetylcholinesterase (AChE) inhibitor was the first FDA approved drug for AD but is discontinued due to hepatotoxicity. Objective: Present research focused on incorporating a flavone to the tacrine nucleus to enhance the anti-Alzheimer’s property of the tacrine with the synergistic effect of flavone which is a very good antioxidant. It is expected that the antioxidant property and hepatoprotective nature of flavones will reduce the hepatotoxic side effect of tacrine. Methods: We designed and synthesized ten flavone substituted tacrine derivatives and evaluated for in vitro AChE and BuChE inhibitoy activity by modified Ellman’s method using eeAChE and eqBuChE. In vitro antioxidant activity was studied by DPPH radical scavenging assay. Molecular modeling studies were conducted in Schrodinger and AutoDock Vina with TcAChE(PDB ID:1H23),hAChE(PDB ID:4EY7) and hBuChE(PDB ID:4TPK). Results: All the compounds exhibited potent inhibitory effect on AChE and BuChE with IC50 values in μM concentration. The compounds exhibited very good antioxidant activity in DPPH radical scavenging assay. Among the compounds the compound AF1 showed highest activity with IC50 value of 0.93 μM for AChE and 1.48 μM for BuChE and also showed significant antioxidant activity (2.6 nM). A correlation graph was plotted for IC 50 values vs Dock score and the results are promising with r2 values of 0.62 and 0.73 for AChE and BuChE inhibition respectively which proved the reliability of docking approaches. Conclusion: The results highlighted the multifunctional nature of the novel Tacrine-Flavone hybrids and they may be promising MTDL for AD.

Background: Pyrimidine derivative has evinced its biological importance in targeting lung cancer by inhibiting neutrophil elastase. Methods: All THPM derivatives were synthesized by the grindstone method at ambient temperature followed by molecular docking study for efficient binding interaction of THPM compounds by targeting human neutrophil elastase (HNE) (PDB ID: 5A0A) and In-silico ADMET study using PkCSM. Moreover, all synthesized compounds were characterized by spectroscopy techniques and screened for anti-cancer activity using in vitro HNE assay kit. Results: We reported a one-pot solvent-free mechanochemical approach for synthesizing tetrahydropyrimidine (THPM) derivatives from various aromatic aldehydes, ethyl cyanoacetate, and urea followed by in silico study and evaluation against human neutrophil elastase (HNE) for treatment of lung cancer. We calibrated the best molecules that bound to specific targets more efficiently using a molecular docking approach and provided the desired efficacy. In-silico ADMET studies revealed that all best-scored compounds had drug-like characteristics for potential use as human neutrophil elastase inhibitors (HNE) in lung cancer treatment. Additionally, the in vitro studies revealed that compounds 1, 2, and 8 show potent HNE inhibitory activity for lung cancer treatment. Conclusion: In a nutshell, the tetrahydropyrimidine (THPM) scaffold and its derivatives may serve as potential HNE inhibitors for the development of a promising anti-cancer agent.

Background: Through this study, the Chemical composition realized by UHPLC-DADESI- MSn allowed the detection of different phenolic compound groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 M^pro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking. Objective: The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects. Methods: Chemical composition was realized by UHPLC-DAD-ESI-MSn, and the inhibition of the main protease (CL3 M^pro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 was studied using molecular docking with Autodock Vina software. ADMET analysis was carried out. Results: The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1μM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drug candidates. Conclusion: This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves are studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.

Background: Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for escaping from G1/S cell cycle arrest in HPV-infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site. Objective: To design a peptide inhibitor targeting HPV E7 through an in silico approach. Methods: In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was further investigated in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome, and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptides. Results: In the in silico approach, a 9-amino acids peptide sequence formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines, where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%) and a reduction of cells in the G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor. Conclusion: A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb can inhibit HPV E7 by causing a cell accumulation effect in G0/G1, and S phases of the cell cycle in the HPV transformed cell lines. These findings could contribute to HPV E7 peptide inhibitor in the future.