Letters in Drug Design & Discovery - Volume 18, Issue 8, 2021

COVID-19 outbreak has hit the world worst at the start of 2020, as of December 11, 2020, more than 1.5 million people have died and more than 68.8 million people have been infected globally. SARS-CoV-2 induces mild to severe progressive respiratory pneumonia, leading to failure of different body organs and ultimately death. Hitherto, there are no specific and potential therapeutic agents available against the virus. The spike protein is a type I surface glycoprotein facilitating entry of the virus into the host cell via hACE2 receptors. The two subunits of the spike protein have a polybasic link as cleavage site (PRAR) in SARS-CoV-2, with an additional attachment of O-linked glycans. SARS-CoV and SARS-CoV-2 have 76.5% similarity in amino acid sequences. The pathogenesis and viral entry of SARS-CoV-2 are different from SARS-CoV, therefore, it is a dire need of time to develop a target-based treatment. Alternative strategies and multidisciplinary research approaches are crucial for developing new antiviral and improved therapies against COVID-19. Nanotechnology has opened new horizons for evaluating the biological properties and efficacy of different materials having a biological origin, such as Nigella sativa. It contains various active components such as thymoquinone, thymol, thymohydroquinone, and dithymoquinone with different biological potentials. Metallic nanomaterials have been reported to exhibit antiviral activities against various strains. Understanding molecular interactions and modifying the surface properties of nanomaterials with optimum activity may result in the development of novel antiviral therapies.

Background: Malaria is one of the most important infectious diseases in the world. The most severe form of malaria in humans is caused by Plasmodium falciparum. Malaria is a worldwide health problem, with 214 million new cases in 2015 and 438,000 deaths, most of which are in Africa. Therefore, there is an urgent need for novel, low-toxic, more specific inhibitors to find new antimalarial agents. A promising target for antimalarial drug design is falcipain-2, a cysteine protease from P. falciparum that has received considerable attention due to its key role in the life cycle of the parasite. Materials and Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR) models of 39 peptidyl vinyl sulfone cysteine protease inhibitors was constructed using Topomer CoMFA. Topomer Search was employed to virtually screen lead-like compounds in the ZINC database. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between peptidyl vinyl sulfone cysteine protease inhibitors and active site residues. Results: The non-cross correlation coefficient (r²), the interaction validation coefficient (q²) and the external validation (r²pred) were 0.902, 0.685 and 0.763, respectively. The results showed that the model not only had good estimation stability but also good prediction capability. 22 new molecules were obtained, whose predicted activity is higher than the template molecules. The results showed that the Topomer Search technology can be effectively applied to screen and design new peptidyl vinyl sulfone cysteine protease inhibitors. Molecular docking showed extensive interactions between peptidyl vinyl sulfone cysteine protease inhibitors and residues of LYS24, ASP21, LYS59, and ASP17 in the active site. Conclusion: 39 peptidyl vinyl sulfone cysteine protease inhibitors were used in the 3D-QSAR study. Topomer CoMFA 3D-QSAR method was used to build the model, and the model was well predicted and statistically validated. The design of potent new inhibitors of cysteine protease can get useful insights from these results.

Background: Kinase enzymes are reported to be very implicated in cancer. Polo-like kinase 1 (PLK1) is a protein kinase with a marked role in tumorigenesis and its inhibition is a promising anticancer therapeutic development strategy. Objective: The purpose of this study was de novo design of new PLK1 inhibitors using in-silico approach. Methods: A virtual compound library based on known inhibitors was designed using BREED algorithm. Molecules were geometrically optimized then filtered according to lead-like properties using QiqProp. Receptor-ligand complex-based pharmacophore model was generated with Phase and used to virtually screen the new virtual database. Glide multistage molecular docking simulations were performed for the resulted compounds followed with a Prime MM-GBSA minimization. Results: Two compounds (prd-comp 1-2) showed acceptable binding poses with a higher docking score than known inhibitor BI2536. MM-GBSA study confirmed that the leads have better binding energy than reference ligands. All leads bind to the key amino acids Cys133, Leu59, with a focus on molecule prd-comp1, proposed to have better affinity due to direct H-bond with Asp194. Conclusion: Modifying hydration pattern of target protein by displacing water molecule is suggested to be a promising strategy for designing new PLK1 inhibitors. This applied methodology and the retrieved hits could be useful in the design of potent inhibitors of PLK1 as antitumoral agents.

Background: Flavonoids are an important group of natural products because they possess various biological activities such as antioxidant, anti-inflammatory, and anti-cancer. The modification of their structure could improve their biological activities. The nitro group is included in diverse pharmaceuticals with various biological activities, such as anti-cancer and anti-inflammatory agents. Objective: The study aimed to introduce a nitro group into the structure of flavonoids in order to observe how their anti-proliferative, antioxidant, and anti-inflammatory activities change. Methods: In this investigation, we established diverse conditions of aromatic nitration of chrysin (1), quercetin (2), and naringin (3) flavonoids using bismuth (III) nitrate, acetic acid or silica gel, and NOx gases. The anti-proliferative activity in CaSki, MDA, and SK-LU-1 cancer cell lines and the anti-inflammatory activity and antioxidant activity of flavonoids and nitro derivatives were evaluated as well. Results: As a result, mild nitration conditions were established, and 8-nitrochrysin, 5’nitroquercetin, and 3’nitronaringin were obtained. The number and hydroxyl group position in the flavonoid are important to carry out the nitration reaction. Although chrysin showed higher anti-proliferative activity than quercetin and naringin, the introduction of the nitro group at C-8 did not improve its antiproliferative, antioxidant, and anti-inflammatory activities. On the other hand, the introduction of the nitro group at C-5#141;'in quercetin structure was important to improve its antioxidant and antiproliferative activities on cancer cell lines. The introduction of the nitro group at C-3’ in naringin improved its anti-inflammatory activity, but not its antioxidant and anti-proliferative activities. Chrysin, 8-nitrochrysin, quercetin, and 5’-nitroquercetin did not show necrotic activity. Conclusion: The introduction of a nitro group into flavonoids structure improved their antiproliferative, antioxidant, and anti-inflammatory activities. These results promote future investigations of structural modification on 2-phenylbenzopyran skeleton to optimize their biological activity.

Background: Antioxidants are small molecules that prevent or delay the process of oxidations caused by highly reactive free radicals. These molecules are known for their ability to protect various cellular architecture and other biomolecules from oxidative stress and free radicals. Thus, antioxidants play a key role in the prevention of oxidative damages caused by highly reactive free radicals. Methods: In the present study, a series of previously synthesized heterocyclic 2-aryl-4(3H)- quinazolinone derivatives 1-25 were screened for antioxidant activity by employing in vitro DPPH and superoxide anion radical scavenging activities. ROS inhibitory activities were also evaluated by serum-opsonized zymosan activated whole blood phagocytes and isolated neutrophils. Cytotoxicity studies were carried out by employing an MTT assay against the 3T3 cell line. Results: Most of the 2-aryl-4(3H)-quinazolinone derivatives showed potent antioxidant activities in superoxide anion radical scavenging assay with IC50 value ranging between 0.57 μM - 48.93 μM, as compared to positive control quercetin dihydrate (IC50 = 94.1 ± 1.1 μM ). Compounds 5, 6, and 14 showed excellent activity in DPPH assay. Compounds 5-8, 12-15, 17, and 20 showed promising activities in the ROS inhibition assay. All compounds were found to be non-cytotoxic against the 3T3 cell line. Structure antioxidant activity has been established. Conclusion: It can be concluded that most of the heterocyclic 2-aryl-4(3H)-quinazolinone derivatives 1-25 are identified as promising antioxidant agents that are capable of fighting against free radicals and oxidative stress. Thus, they can serve as a lead towards treating oxidative stress and related pathologies.

Aims: A pharmacophore based in silico study for screening out Human Acyl-CoA cholesterol acyltransferase (ACAT) inhibitors. Background: Human Acyl-CoA cholesterol acyltransferase (ACAT) plays an important role in catalysis of reaction which converts cholesterol into cholesteryl esters and long-chain fatty acyl coenzyme A. The inhibition of ACAT has therapeutically potential roles in hypercholestrolemia, atherosclerosis and coronary heart disease. Objective: As no 3D structure of Human Acyl-CoA cholesterol acyltransferase (ACAT) is reported, ligand based design of the inhibitors is required that which converts cholesterol into cholesteryl esters. Methods: For better understanding of essential chemical features for ACAT inhibition and identifying novel inhibitors, a three-dimensional (3D) chemical-feature-based quantitative QSAR pharmacophore model for available ACAT inhibitors have been developed for first time using Discovery Studio 2.5. Results: The best model (Hypo1) having lowest total cost (84.14), highest cost difference (69.67), highest correlation coefficient (0.94), and lowest RMS (1.15Å), constitutes of one hydrogen bond acceptor, one hydrogen bond donor, two hydrophobic aromatic and one hydrophobic aliphatic feature. The pharmacokinetic properties and toxicities of top 10 active hits obtained from virtual screening were predicted for ZINC33073636 and ZINC33073625. Conclusion: These studies thus provide a pharmacophore model, which will be helpful in designing novel human ACAT inhibitors.

Background: The fish pathogen Aeromonas hydrophila is fast acquiring resistance to commonly employed antibiotics in aquaculture. This development has compelled the aquaculture sector to identify and develop new therapeutics to manage the pathogen. Methods: In this study, the protein 3-deoxy-d-manno-2-octulosonic acid (Kdo) transferase of A. hydrophila involved in the biosynthesis of the cell wall was studied in-silico as a potential drug target to control this pathogen. The three-dimensional structure of Kdo transferase was predicted by homology modelling using the Modellar 9.15. A total of 7682 natural compounds and 55 known Gram-negative bacterial inhibitors were virtually screened. Laboratory evaluation of inhibitory effects of identified inhibitors against A. hydrophila was performed using extracts from tea leaves and Astragalus by standard disc diffusion method. Results: A molecular model of putative virulence factor Kdo was derived by homology modelling. Eleven compounds were found to be potential inhibitors of Kdo. Among natural compounds, LArabinose and Flavan-3,4-diol were identified as the putative therapeutic agents. In the disc diffusion test, the zones of inhibition were observed at 2 mg/ml concentrations for tea leaves extracts and 8 mg/ml for Astragalus, suggesting the inhibitory effects of these extracts. Conclusion: The study shows the utility of essential enzymes such as the protein Kdo transferase as a putative drug target and the potential application of natural compounds in the control of pathogens in aquaculture without the need to use synthetic antimicrobial compounds.

Aims: The present study aimed to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies were molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties, and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop, and phase application of Schrodinger, respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) were excellent products to bind with their respective targets such as 6LU7, 6M71, and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside interacted well with all the three proteins; these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and invivo studies could be carried out to provide better drug therapy.