Letters in Drug Design & Discovery - Volume 18, Issue 7, 2021

Since December 2019, the prevalence of novel coronavirus infection (named as COVID- 19 by WHO on Feb 11, 2020) has become a growing healthcare concern worldwide. On March 11, 2020, the WHO declared COVID-19 a global pandemic. As no specific approved treatment options are available for the COVID-19 infection, several existing antiviral drugs in combination with others have become the mainstay therapy. The targets for the treatment of the infection include viral targets such as polymerases, spike glycoproteins, membrane proteins, and viral envelope and host targets such as host proteases and host receptors. Antiviral agents, immunomodulatory agents, and empiric broad-spectrum antibiotics can be used as treatment therapies for the infection. Convalescent plasma therapy has also been proposed as an effective treatment for COVID-19. Additionally, many studies are ongoing to develop a potent and effective vaccine that completely blocks SARS-CoV-2. Nevertheless, prevention of spread of the virus remains the first and foremost step towards controlling and managing the coronavirus infection.

Schistosomiasis is a waterborne tropical disease caused by infection with parasitic worms of the Schistosoma genus resulting in significant morbidity in the Middle East, South America, Southeast Asia and, mostly, in sub-Saharan Africa. For over 30 decades, this disease has been on a gradual rise, claiming thousands of lives and disfiguring its sufferers. Currently, over 280 000 mortalities per annum are attributed to this disease, with about 207 million reported cases of infection worldwide. In addition to these overwhelming statistics, infection caused by S. haematobium has been reported to predispose its sufferers to cancer of the bladder. Bladder cancer is regarded as the most common type of cancer in the urinary system, with relatively high incidence, progression and mortality rates despite the efforts put into providing optimal treatment for the disease. Despite the diagnostic and treatment options already put into place, there is still a growing need to develop alternative strategies to combat these diseases. The high expression levels of a group of molecular chaperones, known as heat shock proteins, can be used as biomarkers of infection and can consequently play a role in the development of alternative treatment methods.

Background: The recent outbreak caused by SARS-CoV-2, known as COVID-19, has been cataloged as a global catastrophe due to the growing number of infected cases and deaths since November 2019; this infectious, contagious disease, to date, does not have a vaccine or specific treatment available, which is why the number of cases continues to increase. SARS-CoV-2 infects humans as a result of the interaction between the receptor-binding domain of the viral spike protein and the receptor of the angiotensin-converting enzyme-2 (rACE2), located predominantly in the alveolar cells. Objective: This study aims to identify inhibitory peptides of the protein-protein interaction between the receptor-binding-domain of the spike protein of SARS-CoV-2 and the angiotensin-converting enzyme-2 receptor through computational tools. Methods: Through the Research Collaboratory for Structural Bioinformatics protein database, crystals were selected and interaction models were carried out between the viral protein and the ACE2; thereafter, the study designed inhibitory peptides of the interaction through the Rosetta web server, validated their interaction through ClusPro and, finally, determined the theoretical physicochemical and cytotoxic properties. Results: A protein complex was generated and modeled through ClusPro; the balanced model was selected with the lowest binding energy. From the protein interactions of each of the crystals and from the model, eight peptides of 20 residues were obtained. The theoretical evaluation showed non-toxic peptides, six soluble in water, and two insoluble. Conclusion: We found eight peptides that interacted with the receptor-binding-domain of the spike protein of SARS-CoV-2, which could avoid contact with the cell receptor and generate interference in the infection process.

Background: Remdesivir, a drug in use for Ebola it is already tested in clinical trials phase III. Objective: To evaluate any other possible related structures with similar properties that could be used in clinical trials for COVID-19. Methods: Molecular docking studies, DFT studies, ADMET studies. Result: Saquinavir is a chemical structure with similar and even a better chemical activity that drugs that entered clinical trials for COVID-19. Conclusion: Saquinavir should be entered the clinical trials for the treatment of the COVID-19 disease, as it has shown excellent binding affinities to SARS Cov-2 RNA depended polymerase and forms stable complexes with the protein and could possible inhibited its action.

Background: Natural sesquiterpene lactones are an important class of heterocyclic compounds in drug discovery since they possess a wide range of biological properties, including antibacterial activity. Objective: The objective of this study was to synthesize isoalantolactone derivatives with a furo[2,3-d] pyrimidin-2-оne moiety, and to evaluate their antibacterial and antiviral activity. Methods: The Sonogashira cross-coupling and subsequent Ag-catalyzed cyclization reactions were used forthe synthesis. The antibacterial activity and the ability to inhibit biofilms formation on E. coli, S. aureus, A. viscosus, P. aeruginosa, and E. faecalis bacterial strains were evaluated in this study. A study of the molecular interactions of new compounds with the multiple virulence factor regulators was performed using docking simulations. The anti-viral activity against influenza A virus and human orthopneumovirus H-2Ц#144; was also studied. Results: The in vitro anti-bacterial activity for compound 4 (MIC = 58.33 ± 4.41 μg/mL) concerning E. coli and compound 5 (MIC = 96.5 ± 3.25 μg/mL) against A. viscosus and the inhibition of biofilm formation for compounds 2, 4, and 5 on E. coli, S. aureus, P. aeruginosa, and E. faecalis bacterial strains, have been of interest for the search of improved anti-microbial agents. Compound 3 possessed antiviral activity against human orthopneumovirus H-2Ц#144; with SI >33. The activity of the new type of hybrid compounds is dependent on the substituent in the 6th position of the furo[2,3-d] pyrimidin-2-one fragment. Conclusion: The decoration of isoalantolactone with a furo[2,3-d]pyrimidin-2-one fragment led to the development of antiviral and antimicrobial agents. Due to the antimicrobial activity, pyridine-4- yl substituted isoalantolactone-furopyrimidinone hybrid is considered as a candidate compound to participate in further research.

Background: The era of drug discovery suggested the designing of “hybrid drugs,” which acquired recognition in the field of medicinal chemistry due to its influential role in preserving different health challenges. Objective: A new series of chalcone derivatives 4a-4i, bearing isoxazole moieties, were designed and synthesized with microwave irradiation, which were biologically evaluated for their activity on NCI- 60 cell-lines to check efficacy in anti-cytotoxic effect. Methods: The required diverse acetophenone molecule was prepared by chloro-amine coupling using lansoprazole (lanso chloro) drug intermediate, i.e., 4-(2,2,2-trifluoroethoxy)-2-(chloromethyl)-3- methylpyridine engaged in the reaction with various aryl aldehydes (2a-2i) in the primary media gave fluoro contained chalcone (3a-3i). The desired isoxazoles (4a-4i) were synthesized by MW (microwave irradiation) based reaction using hydroxylamine for cyclization purposes. Results: The espoused scheme resulted in good yields of a new set of isoxazole-chalcone conjugates with potent cytotoxic activity, which were found in compounds 4h and 4i against the Leukemia RPMI-8226 (With GI50 Values ≈ -10 μg/ml) cancer cell line and the Non-Small Cell Lung Cancer HOP-92 (With GI50 Values ≈ -25 μg/ml) cancer cell line. Conclusion: The optimization of the reaction indicated that the MW based reaction progress was an efficient and time-saving process for the course of isoxazole synthesis. An anticancer study shows that compounds 4h demonstrated significant anticancer activity.

Background: Visceral leishmaniasis, the most lethal form of Leishmaniasis, is caused by Leishmania donovani in the Indian subcontinent and East Africa. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug-resistant strains. Thus, the discovery of potential targets, successful inhibitors, and improved drug distribution mechanisms for leishmaniasis diagnosis has become a focus. Objective: Hydroperoxide metabolism involving trypanothione, key for the survival of Leishmania, is a validated target for rational drug design. In this study, we aim in silico drug design by targeting tryparedoxin peroxidase (2-Cysperoxiredoxin type) from Leishmania donovani (LdTXNPx) using clioquinol, nelfinavir, and strychnobiflavone as mother compound. Clioquinol, nelfinavir are known for their anti-leishmanial activity and strychnobiflavone showed antileishmanial activity against Leishmania amazonensis and Leishmania infantum amastigotes and promastigotes recently. Methods: On this basis, we constructed protein structure using homology modeling, molecular docking of protein with potential drug candidates, interaction analysis and pharmacophore analysis conducted in this study. Results: We have revealed two compounds i.e. Nelfinavir mesylate and strychnobiflavone, which have desired characteristics in the future drugs for Visceral leishmaniasis. Conclusion: Consistently in the future, we will ratify the efficacy of these compounds, essential animal and clinical trials are needed to be performed. We believe that our present study will help to find efficient and effective therapy for treating Visceral leishmaniasis in humans.

Background: α-Glucosidase is an important hydrolytic enzyme playing a vital role in digestion of carbohydrates. It catalyzes the final step of carbohydrates digestion in biological systems and converts unabsorbed oligosaccharides and disaccharides into monosaccharides, thus resulting in hyperglycemia for diabetic patients. In this respect, it has been considered as a therapeutic target for the treatment of type 2 diabetes since the enzyme inhibition delays carbohydrate digestion and monosaccharide absorption and subsequently reduces postprandial plasma glucose levels. Objective: In this study, fourteen 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives were synthesized and evaluated for their α-glucosidase inhibitory activities. Methods: The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The biological activity and enzyme inhibition kinetic studies were performed by spectrophotometrical method using microplate reader. Physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. Results: The biological activity results revealed that all of the synthesized compounds showed more potent α-glucosidase inhibitory activity in the range of IC50 = 58 ± 2 - 375 ± 15 μM when compared to the standard drug acarbose (IC50 = 892 ± 7 μM). Among the tested compounds, compound 12 bearing chlorine substituent at ortho position on N-phenyl ring displayed the highest inhibition with an IC50 value of 58 ± 2 μM against α-glucosidase. Furthermore, the enzyme inhibition kinetic study of the most active compound 12 indicated that the compound inhibited the α-glucosidase enzyme as uncompetitive with a Ki value of 63.46 μM. On the other hand, physicochemical and drug-likeness properties of selected compounds were predicted by in silico method. According to the results, it can be speculated that synthesized 2-phenylaminoquinazolin-4(3H)-one derivatives possessed favorable drug-likeness and pharmacokinetic profiles. Conclusion: In the light of results, 2-(substitutedphenylamino)quinazolin-4(3H)-one derivatives may serve as lead compounds to develop novel α-glucosidase inhibitors.

Aim: To investigate and validate the potential target proteins for drug repurposing of newly FDA approved antibacterial drug. Background: Drug repurposing is the process of assigning indications for drugs other than the one(s) that they were initially developed for. Discovery of entirely new indications from already approved drugs is highly lucrative as it minimizes the pipeline of the drug development process by reducing time and cost. In silico driven technologies have made it possible to analyze molecules for different target proteins which are not yet explored. Objective: To analyze possible target proteins for drug repurposing of lefamulin and their validation. Also, in silico prediction of novel scaffolds from lefamulin has been performed for assisting medicinal chemists in future drug design. Methods: A similarity-based prediction tool was employed for predicting target protein and further investigated using docking studies on PDB ID: 2V16. Besides, various in silico tools were employed for the prediction of novel scaffolds from lefamulin using scaffold hopping technique followed by evaluation with various in silico parameters viz., ADME, synthetic accessibility and PAINS. Results: Based on the similarity and target prediction studies, renin is found as the most probable target protein for lefamulin. Further, validation studies using docking of lefamulin revealed the significant interactions of lefamulin with the binding pocket of the target protein. Also, three novel scaffolds were predicted using the scaffold hopping technique and found to be in the limit to reduce the chances of drug failure in the physiological system during the last stage approval process. Conclusion: In the future, lefamulin may assist in the development of the renin inhibitors, and also, three possible novel scaffolds with a good pharmacokinetic profile can be developed into renin inhibitors and for bacterial infections.

Background: The MurA enzyme, enolpyruvyl UDP-N-acetylglucosamine transferase, is one of the targeted proteins by antibiotics for effective treatment of diseases provided by pathogenic bacteria. It plays a key role in the cell wall biosynthesis of Gram-positive bacteria such as Enterococcus faecalis. Butein is a flavonoid that showed antioxidant and anticancer activities, but recently it is a promising antibacterial agent and reported can inhibit E. faecelis, Eschericia coli, and Mycobacterium tuberculosis. It was isolated from medicinal plants, including Sarang Semut (Myrmecodia pendans). However, the molecular mechanism of butein inhibits bacteria that is no clear. Objective: This study aims to predict the molecular action of the butein against MurA, catalyzing the first step of peptidoglycan biosynthesis. Material and Methods: Butein isolation used a combinational separation technique and characterization using spectroscopic methods. Then, in silico method used was virtual screening using programs including Autodock Vina in PyRx, protein. plus, and ligplots. Butein and UDP-N-acetylglucosamine (UNAG as a positive control) act as ligand were subject binding to 3KQJ MurA as protein. To evaluate in vitro antibacterial activity, we used the Kirby-Bauer method. Results: Butein from M. pendans is a potential compound to inhibit the MurA with binding affinity - 7.6 kcal.mol-1. It is lower than UNAG but higher than Fosfomycin as a MurA inhibitor. Butein attaches to MurA in the same position as UNAG so that it concludes that both is a competitive inhibitor. Meanwhile, in vitro study showed that butein inhibits the E. faecalis growth with inhibit zone of 8.37 mm at 1 mg/ml. Conclusion: Butein as a potent antibacterial agent through blocking MurA enzyme in cell wall formation.