Proposal of novel ApoE4 inhibitors from the natural spice Cinnamon for the treatment of Alzheimer's disease: Ab initio molecular simulations.

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, is a major factor contributing to cognitive impairment in older adults. Current therapeutic treatments can only relieve the symptoms of AD, but they cannot stop the progression of the disease because it takes a long time for clinical symptoms to manifest. Therefore, it is essential to develop effective diagnostic strategies for early detection and treatment of AD. As the most common genetic risk factor for AD, apolipoprotein E4 (ApoE4) is present in more than half of patients with AD, and it can be a target protein for AD therapy. We used molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and Cinnamon-derived compounds. Of the 10 compounds, epicatechin was found to have the highest binding affinity to ApoE4 because the hydroxyl groups of epicatechin form strong hydrogen bonds with the Asp130 and Asp12 residues of ApoE4. Therefore, we proposed some epicatechin derivatives by adding a hydroxyl group to epicatechin and studied their interactions with ApoE4. The FMO results indicate that the addition of a hydroxyl group to epicatechin increases its binding affinity to ApoE4. It is also revealed that the Asp130 and Asp12 residues of ApoE4 are important for the binding between ApoE4 and the epicatechin derivatives. These findings will help propose potent inhibitors against ApoE4, leading to a proposal for effective therapeutic candidates for AD.

Natural inhibitors for severe acute respiratory syndrome coronavirus 2 main protease from Moringa oleifera, Aloe vera, and Nyctanthes arbor-tristis: molecular docking and ab initio fragment molecular orbital calculations.

The novel coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide, and new drug treatments for COVID-19 are urgently required. To find the potential inhibitors against the main protease (Mpro) of SARS-CoV-2, we investigated the inhibitory potential of naturally occurring compounds from the plants Moringa oleifera, Aloe vera, and Nyctanthes arbor-tristis, using molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations. Of the 35 compounds that we simulated, feralolide from Aloe vera exhibited the highest binding affinity against Mpro. Therefore, we proposed novel compounds based on the feralolide and investigated their binding properties to Mpro. The FMO results indicated that the introduction of a hydroxyl group into feralolide significantly enhances its binding affinity to Mpro. These results provide useful information for developing potent Mpro inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02021-y.

Compounds Identified from Marine Mangrove Plant (Avicennia alba) as Potential Antiviral Drug Candidates Against WDSV, an In-Silico Approach.

Walleye dermal sarcoma virus (WDSV) is a type of retrovirus, which affects most of the adult walleye fishes during the spawning time. The virus causes multiple epithelial tumors on the fish's skin and fins that are liable for more than 50% of the mortality rate of fish around the world. Till now, no effective antiviral drug or vaccine candidates have been developed that can block the progression of the disease caused by the pathogen. It was found that the 582-amino-acid (aa) residues long internal structural gag polyprotein of the virus plays an important role in virus budding and virion maturation outside of the cell. Inhibition of the protein can block the budding and virion maturation process and can be developed as an antiviral drug candidate against the virus. Therefore, the study aimed to identify potential natural antiviral drug candidates from the tropical mangrove marine plant Avicennia alba, which will be able to block the budding and virion maturation process by inhibiting the activity of the gag protein of the virus. Initially, a homology modeling approach was applied to identify the 3D structure, followed by refinement and validation of the protein. The refined protein structures were then utilized for molecular docking simulation. Eleven phytochemical compounds have been isolated from the marine plant and docked against the virus gag polyprotein. Three compounds, namely Friedlein (CID244297), Phytosterols (CID12303662), and 1-Triacontanol (CID68972) have been selected based on their docking score -8.5 kcal/mol, -8.0 kcal/mol and -7.9 kcal/mol, respectively, and were evaluated through ADME (Absorption, Distribution, Metabolism and Excretion), and toxicity properties. Finally, molecular dynamics (MD) simulation was applied to confirm the binding stability of the protein-ligands complex structure. The ADME and toxicity analysis reveal the efficacy and non-toxic properties of the compounds, where MD simulation confirmed the binding stability of the selected three compounds with the targeted protein. This computational study revealed the virtuous value of the selected three compounds against the targeted gag polyprotein and will be effective and promising antiviral candidates against the pathogen in a significant and worthwhile manner. Although in vitro and in vivo study is required for further evaluation of the compounds against the targeted protein.

Improvement of conventional anti-cancer drugs as new tools against multidrug resistant tumors.

Multidrug resistance (MDR) is the dominant cause of the failure of cancer chemotherapy. The design of antitumor drugs that are able to evade MDR is rapidly evolving, showing that this area of biomedical research attracts great interest in the scientific community. The current review explores promising recent approaches that have been developed with the aim of circumventing or overcoming MDR. Encouraging results have been obtained in the investigation of the MDR-modulating properties of various classes of natural compounds and their analogues. Inhibition of P-gp or downregulation of its expression have proven to be the main mechanisms by which MDR can be surmounted. The use of hybrid molecules that are able to simultaneously interact with two or more cancer cell targets is currently being explored as a means to circumvent drug resistance. This strategy is based on the design of hybrid compounds that are obtained either by merging the structural features of separate drugs, or by conjugating two drugs or pharmacophores via cleavable/non-cleavable linkers. The approach is highly promising due to the pharmacokinetic and pharmacodynamic advantages that can be achieved over the independent administration of the two individual components. However, it should be stressed that the task of obtaining successful multivalent drugs is a very challenging one. The conjugation of anticancer agents with nitric oxide (NO) donors has recently been developed, creating a particular class of hybrid that can combat tumor drug resistance. Appropriate NO donors have been shown to reverse drug resistance via nitration of ABC transporters and by interfering with a number of metabolic enzymes and signaling pathways. In fact, hybrid compounds that are produced by covalently attaching NO-donors and antitumor drugs have been shown to elicit a synergistic cytotoxic effect in a variety of drug resistant cancer cell lines. Another strategy to circumvent MDR is based on nanocarrier-mediated transport and the controlled release of chemotherapeutic drugs and P-gp inhibitors. Their pharmacokinetics are governed by the nanoparticle or polymer carrier and make use of the enhanced permeation and retention (EPR) effect, which can increase selective delivery to cancer cells. These systems are usually internalized by cancer cells via endocytosis and accumulate in endosomes and lysosomes, thus preventing rapid efflux. Other modalities to combat MDR are described in this review, including the pharmaco-modulation of acridine, which is a well-known scaffold in the development of bioactive compounds, the use of natural compounds as means to reverse MDR, and the conjugation of anticancer drugs with carriers that target specific tumor-cell components. Finally, the outstanding potential of in silico structure-based methods as a means to evaluate the ability of antitumor drugs to interact with drug transporters is also highlighted in this review. Structure-based design methods, which utilize 3D structural data of proteins and their complexes with ligands, are the most effective of the in silico methods available, as they provide a prediction regarding the interaction between transport proteins and their substrates and inhibitors. The recently resolved X-ray structure of human P-gp can help predict the interaction sites of designed compounds, providing insight into their binding mode and directing possible rational modifications to prevent them from becoming P-gp drug substrates. In summary, although major efforts were invested in the search for new tools to combat drug resistant tumors, they all require further implementation and methodological development. Further investigation and progress in the abovementioned strategies will provide significant advances in the rational combat against cancer MDR.

Alignment-based design and synthesis of new antimicrobial Aurein-derived peptides with improved activity against Gram-negative bacteria and evaluation of their toxicity on human cells.

Considering the worldwide increasing prevalence of resistance to traditional antibiotics, it is necessary to find new antibiotics to deal with this issue. Recently, antimicrobial peptides (AMPs) have been proposed as new antimicrobial agents. Aureins are a family of AMPs that are isolated from Green and Golden Bell Frogs. These peptides have a favorable antibacterial activity against Gram-positive bacteria. We designed two peptides derived from natural Aurein enjoying alignment-based design method. After synthesis of the peptides, their secondary structure was checked by circular dichroism. Consequently, the antibacterial effects of these peptides were investigated by determining the minimum inhibitory concentration (MIC) and bactericidal concentration. Eventually, the toxicity of these peptides was determined by MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide) assay on normal human skin cells (Hu02 cell line). Natural Aurein1.2 was used as a natural control to compare the properties in all stages. The results indicated that these new peptides had medium-upward antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis (MIC of 8-64 µg/mL) and weak bactericidal activity against Staphylococcus aureus (MIC of 128-256 µg/mL). Also, MTT assays results showed that AureinN2 is less toxic than AureinN1 and Aurein1.2. Toxicity of AureinN2 for Hu02 cell lines was between 20 and 40% at the concentration of 8-500 µg/mL. In this study, we were able to improve antimicrobial activity of two synthetic derivatives of the Aurein family against Gram-negative bacteria by using machine-learning algorithm and other in silico methods.

Therapeutic value of steroidal alkaloids in cancer: Current trends and future perspectives.

Discovery and development of new potentially selective anticancer agents are necessary to prevent a global cancer health crisis. Currently, alternative medicinal agents derived from plants have been extensively investigated to develop anticancer drugs with fewer adverse effects. Among them, steroidal alkaloids are conventional secondary metabolites that comprise an important class of natural products found in plants, marine organisms and invertebrates, and constitute a judicious choice as potential anti-cancer leads. Traditional medicine and modern science have shown that representatives from this compound group possess potential antimicrobial, analgesic, anticancer and anti-inflammatory effects. Therefore, systematic and recapitulated information about the bioactivity of these compounds, with special emphasis on the molecular or cellular mechanisms, is of high interest. In this review, we methodically discuss the in vitro and in vivo potential of the anticancer activity of natural steroidal alkaloids and their synthetic and semi-synthetic derivatives. This review focuses on cumulative and comprehensive molecular mechanisms, which will help researchers understand the molecular pathways involving steroid alkaloids to generate a selective and safe new lead compound with improved therapeutic applications for cancer prevention and therapy. In vitro and in vivo studies provide evidence about the promising therapeutic potential of steroidal alkaloids in various cancer cell lines, but advanced pharmacokinetic and clinical experiments are required to develop more selective and safe drugs for cancer treatment.

Exploration of Umbelliferone Based Derivatives as Potent MAO Inhibitors: Dry vs. Wet Lab Evaluation.

BACKGROUND: Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson's disease. OBJECTIVE: We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. METHOD: A series of different umbelliferone derivatives was designed and synthesized, and the derivatives were screened for hMAO-A and hMAO-B inhibition. Moreover, the mechanistic insight for enzyme- compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. RESULTS: Compound 5 with bromo 5-bromo-isatin exhibited a remarkable hMAO-A inhibitory potential (7.473±0.035 µM and the selectivity index of 0.14) revealing the impact of hybrid coumarin and 5- bromo-2-oxoindolin-3-yl ring with hydrazine linker on the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32±0.044µM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2-oxo-2H-chromen ring led the important binding infractions within the hMAO active site. CONCLUSION: Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants.