Letters in Drug Design & Discovery - Volume 18, Issue 9, 2021

Increased numbers of reported cases of Mycobacterium tuberculosis (Mtb) resistance to the generally used antibiotics demand to identify novel therapeutic entities for better control of Tuberculosis. Most of the Structure-based Drug Discovery (SBDD) works reported earlier had screened compounds against a single drug target to avoid any off-target binding and related complications. Because of the development of Multi-Drug Resistant and Extensively Drug-Resistant strains of Mtb and looking into the incurable pathologies, targeting the right drug target with a promising ligand data set will result in effective therapeutics. Simultaneously, traditional knowledge-based drugs have earned little success in developing anti-tuberculosis drugs in recent studies. Combining the right-target approach and traditional herbal knowledge base, this in silico drug discovery study was carried out where 1236 compounds from two plants, traditionally used for TB treatment, Camellia sinensis, Ginkgo biloba along with the antibacterial compounds of DrugBank Database have been screened against Pantothenate synthetase of Mtb, a well-known drug target for anti-TB therapeutics. Through this analytics, Epigallocatechin gallate (EGCG) of Camellia sinensis has been reported through in silico docking studies and subsequent Molecular Dynamics simulation, as a promising anti-TB candidate due to its affinity towards Pantothenate synthetase of Mtb. EGCG was subjected to ADME-Tox studies as well as 3D QSAR analysis for the detection of its drug-like properties and for the determination of IC50 value. The EGCG showed the IC50 value at 1404 nM, which is quite promising for a plant-origin compound. The selected ligand, EGCG, due to its promising affinity towards Pantothenate synthetase of Mtb with high drug-like properties, justifies its selection as a potential anti-tuberculosis compound.

Background: Coronavirus disease-19 (COVID-19) is a newly emerged pandemic leading to a state of international alert and leaving millions of infections and thousands of deaths all over the world. Analysis of statistics and epidemiological data for the pandemic outcome pinpointed a puzzling influence of human sex on the heterogeneous outcome of COVID-19, where hospital admissions and mortality were higher among males than females. Two theories explained the observed male-biased COVID-19 mortality based on either dosage of immunoregulatory genes coded in X- chromosomes, or on the abundance of the angiotensin-converting enzyme two (ACE2) receptors in males than females. Objective: In our study, we propose a third scenario through virtual screening of direct antiviral effects of sex hormones. Materials and Methods: Updated screening statistics from 47 countries displaying sex-disaggregated data on COVID-19 were employed and visualized in the form of heatmaps depicting sex difference effects on statistics of cases and deaths. Molecular docking and binding simulations of investigated sex steroids against COVID-19 specific proteins were investigated. Results: Analysis of COVID-19 sex-disaggregated data confirmed that male-biased mortality and computer-aided docking found unexpected female sex hormones biased binding against key targets implicated in the life cycle of COVID-19 compared to the male sex hormone testosterone. Other investigated steroids showed promising docking scores, while the male sex hormone exhibited the lowest affinity. Conclusion: Female sex hormones virtually exhibit direct anti-COVID-19 effect, the proposed antiviral effect of sex hormones should be considered to explain the outcomes of mortality. Moreover, the fluctuation of sex hormones influences sex and personal derived-differential response to COVID-19 infection.

Background: Over the years, the xanthone nucleus has been serving as an interesting scaffold for the design of derivatives aiming at anti-inflammatory drug development. Objective: The objective of the current work was to design and synthesize two series of novel 3- (5'-substituted pentyloxy)-1-hydroxy xanthone & 6-(5'-substituted pentyloxy)-1-hydroxy xanthone derivatives. The designed compounds were examined in vivo for anti-inflammatory activity. The effect of the synthesized xanthone derivatives on the serum expression of IL-10 and TNF-α was evaluated to understand the underlying molecular mechanisms. Methods: The title compounds were virtually designed and screened for ADME/T properties and docked onto the COX-2 protein. The synthesis of the xanthone derivatives was achieved by the condensation of salicylic acid derivatives and a suitable phenol in the presence of a mixture of phosphorus pentoxide–methanesulfonic acid as an acylation catalyst. The compounds were evaluated for in vivo anti-inflammatory activity by carrageenan induced paw edema method and serum expression of cytokines was evaluated using ELISA assays. Results: The selected compounds exhibited docking scores ranging between -10.7 to -6.8 (Kcal/mol), respectively, as compared with standard Celecoxib (-7.9 Kcal/mol) and the nonselective COX inhibitor Indomethacin (-6.4 Kcal/mol). Among the tested compounds, 9u has shown the highest activity with 65.6 % reduction in edema (69.8% for Celecoxib). Immunoassay results showed a significant drop in serum TNF-α and an elevation in serum IL-10. Conclusion: The findings highlight that some of the synthesized xanthone derivatives displayed marked anti-inflammatory activity, which can be further investigated to render efficient and novel non-ulcerogenic anti-inflammatory agents.

Background: Pneumonia induced by a novel coronavirus (SARS-CoV-2) was named coronavirus disease 2019 (COVID-19). The Receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein causes invasion of the virus into the host cell by attaching with human angiotensinconverting enzyme-2 (hACE-2), which leads to further infection. Objective: The novel N-(2-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives were designed and synthesized to inhibit the RBD of SARS-CoV-2 spike glycoprotein by applying molecular docking tools. Methods: The synthesized products were characterized by Infrared Spectroscopy (IR) and 1H Nuclear Magnetic Resonance (NMR). Results: All the derivatives were found to have a very good binding affinity between -9 to -10.1 kcal/mol, better than the drugs which are under investigation for the treatment of SARS-CoV-2 infection. Compound F1 formed 4 hydrogen bonds whereas, F4 and F10 formed two hydrogen bonds each with RBD of SARS-CoV-2 spike glycoprotein. All the derivatives were subjected to antimicrobial, antifungal, and antimalarial susceptibility. Conclusion: From the above-obtained results, we have concluded that novel N-(2-aminophenyl)-2,3- diphenylquinoxaline-6-sulfonamide derivatives have excellent potential to inhibit the receptorbinding domain (RBD) of SARS-CoV-2 spike glycoprotein, which is now an attentive target in designing SARS-CoV-2 inhibitors. This scaffold can hold an effective interest in the development of inhibitors for SARS-CoV-2 in the future if drug repurposing fails to serve the purpose.

Background: Allergic diseases are turning into an expanding occurrence around the globe, imposing a socioeconomic burden, causing grimness and even death. Allergen encounter initiates the influx of TH2 cells, triggering the production of TH2 associated cytokines (IL-4, IL-5, and IL-13), which in turn promotes the detrimental allergic inflammation associated with asthma, allergic rhinitis, food allergy, urticaria, atopic eczema, and anaphylaxis. Cytokine alarmins (TSLP and IL-33) produced by epithelial cells play important roles in the promotion of TH2 cell development and the initiation of allergic pathogenesis. Objective: To target cytokine alarmins (TSLP and IL-33) as novel therapeutic proteins, using natural compounds as a potential cure at an early stage of allergic diseases. Methods: Structure-based virtual screening of two large natural compounds databases (Universal Natural product Database (UNPD) and ZINC natural product database) was conducted for the identification of TSLP and IL-33 inhibitors using Autodock Vina followed by rescoring of the hit compounds. using Autodock 4.2 software. In silico physicochemical, pharmacokinetic, and toxicity analyses were conducted to assess the drug-like properties of the hit compounds. The binding mode stability of UNPD116849, ZINC01448143, and ZINC04096134 in the binding pocket of TSLP and IL-33 was probed by all-atom 50 ns molecular dynamics simulation. Results: Five natural compounds (UNPD111, UNPD116849, ZINC01448143, ZINC15957528, and ZINC04096134) containing different structural moieties (steroidal, chromone, benzodioxole, and indole) were identified to inhibit TSLP and IL-33, with limonin (ZINC04096134) found to demonstrate dual inhibitory activity potential. These compounds were found to be drug-like and toxicity-free using in silico Absorption, Distribution, Metabolism, Elimination, and Toxicity (ADME-T) prediction methods. Taken together, this study suggests the dual inhibition potential of limonin (ZINC04096134) against the cytokine alarmins. Conclusion: Five natural compounds with diverse structural moieties (steroidal, chromone, benzodioxole, and indole) were virtually identified as hit compounds against cytokine alarmins (TSLP and IL-33), with limonin showing dual inhibitory potential.