Letters in Drug Design & Discovery - Volume 19, Issue 5, 2022

Background: With reference to COVID-19 pandemic prevailing across the globe, chloroquine and hydroxychloroquine were reported as effective against the disease to some extent. This effectiveness can be attributed to the glycosylation interruption of the Angiotensin-converting enzyme 2 (ACE2) receptor, which is a known target for SARS-CoV-2 entery. On the other hand, studies suggest that the inhibition of ACE2 can be lethal in certain cases, thereby causing cardiovascular disorders, especially in patients already suffering from heart-related diseases. Methods: In this study, the most probable targets (other than ACE2) have been proposed for the treatment of COVID-19 infection by taking chloroquine and hydroxychloroquine as reference drugs. SwissTargetPrediction and PASSonline tools were used in order to achieve this objective. Known drugs against each target possessing close relation to either viral infections or lung disorders were assessed from the DrugBank database, and simultaneous efficacy of these drugs towards other proposed targets has been analyzed. By taking the most effective drugs as a reference, similar compounds were screened from the ChEMBL library by using the SwissSimilarity tool. Finally, molecular docking studies were performed through MOE software by using screened compounds against proposed targets. Results: Four most probable targets have been proposed, which include chemokine receptors (CCRs), dipeptidyl peptidase 4 (DPP4), muscarinic acetylcholine receptors (CHRMs), and histamine Nmethyltransferase (HNMT). Furthermore, it has been evaluated that quinacrine and vildagliptin are effective against most of the proposed targets. By taking vildagliptin as well as quinacrine as reference drugs, further eight compounds with similar effectiveness against these targets have been screened from the ChEMBL library. Molecular docking studies with CCR5, DPP4, and CHRM5 suggest that the quinacrine and its analogue (ChEMBL1782742) as well as vildagliptin and its analogue (ChEMBL511785) are the most suitable compounds as HITs for these targets. Conclusion: It has been established that the quinacrine, ChEMBL1782742, vildagliptin, ChEMBL511785, mavorixafor, atropine, and N-(2-aminoethyl)-1-aziridineethanamine in descending order can be considered as effective drugs for the treatment of COVID-19 infection.

Aims: To expound the mechanisms of selective PARP-1 inhibition by compound10n. Background: Poly ADP-ribose polymerase-1 (PARP-1), due to its role in DNA damage and repair, has been identified as a crucial therapeutic target to attenuate cancer development and progression. Objective: Selective inhibition has remained a focal point in PARP-1 targeting, therefore, we explored the selective inhibitory mechanism of Compound10n. Methods: we employed computational methods for this study. Results: Findings revealed that the inhibitor stabilized the characteristic motion of activated PARP- 1 as evidenced by reductions in residual deviations and structural flexibility. Findings further revealed that compound10n was favorably bound at the active site PARP-1 as supported by the occurrence of strong hydrogen and halogen bonds based on complementarity. These were in addition to aromatic bonds with enhanced ring to ring stability. Steady and high-affinity interactions between the fluorine atom of compound10n and Glu988 could potentiate the selective activity of the compound. Interaction analyses also revealed that inhibitor binding was strongly dependent on electrostatic effects over van der Waal contributions which were relatively minimal. Conclusion: We believe findings from this study will further contribute to the rational structurebased design of highly selective PARP-1 inhibitors.

Background: Besides the viral infections, bacterial infections can cause serious and lifethreatening complications and drug resistance is an important problem to fight bacterial infections. Therefore, it is important to discover novel antimicrobial agents to fight such infections. Objective: Several indole containing antimicrobial drug development studies have been reported in literature that provided strong evidence for good antimicrobial activities against a variety of microorganisms. Taken into consideration from these findings, antimicrobial properties of previously synthesized 16 indole amide derivatives were evaluated by in vitro tests against 14 different microorganisms, and also molecular docking and in silico prediction studies were used to identify structure-activity relationship of compounds. Methods: Antimicrobial activity of compounds was determined by disc diffusion and tube dilution methods. Molecular docking of compounds was studied to determine the relationship between the structure of compounds with DNA gyrase interactions of microorganisms by using the version of Autodock vina 4.2.6. Mol inspiration and Swiss ADME prediction online software programs were also used to identify drug-like properties of compounds. Results: The results showed that some compounds exhibited quite pronounced antibacterial and antifungal activities compared to reference drugs. These results were also supported by molecular docking studies and in silico ADME calculations presented that all tested compounds obey Lipinski’s Rule of Five and are metabolized by CYP450 enzymes. Conclusion: It can be concluded that these results can be taken as a reference in the development of new indole-based antimicrobial agents.

Background: Glycyrrhiza uralensis, also known as liquorice, is a herbal remedy that is traditionally used worldwide for treating respiratory ailments and ameliorating breathing. Objective: The objective of this systematic study was to investigate active ingredients of Glycyrrhiza uralensis and determine its mode of action in silico against severe and acute respiratory complications of respiratory ailments through network pharmacology and molecular docking studies. Methods: TCMSP database search helped retrieve the compounds of Glycyrrhiza uralensis and their protein targets, especially related to respiratory ailments. Subsequently, the protein-protein association was attained as a network by using the STITCH database. Cytoscape and its ClueGO plugin were used to study gene ontology (GO) enrichment. In addition, seven natural compounds were docked in the active site of four different molecular targets; JUN-FOS, COX2, MAPK14 and IL-6, to identify the binding mechanism of ligands under study. Results: TCMSP database search resulted in the retrieval of 280 compounds of Glycyrrhiza uralensis (including formononetin, naringenin, sitosterol, isorhamnetin, kaempferol, quercetin and Glycyrrhizin) and 135 protein targets. A careful study of targets showed that 26 prospective targets (including JUN, FOS, IL6, MAPK14 and PTGS2) related to respiratory ailments were identified. Gene ontology (GO) enrichment analysis resulted in the retrieval of 176 GO terms, which were associated with respiratory ailments. This study proposed that Glycyrrhiza uralensis acts against respiratory ailments through various proteins, such as JUN, FOS, IL6, MAPK14 and PTGS2. Docking results revealed that among all studied ligands, the flavonoid-based compounds isorhamnetin and kaempferol form stronger complexes with JUN-FOS-DNA, MAPK-14, and IL-6 proteins (Cscore=6.81, 4.27, and 4.77, respectively) and the saponin based compound glycyrrhizin (Cscore=13.07) demonstrated stronger binding affinity towards COX2 enzyme. Conclusion: Conclusively, isorhamnetin, kaempferol and glycyrrhizin in Glycyrrhiza uralensis may regulate several signaling pathways through JUN-FOS-DNA, MAPK-14, and IL-6, which might play a therapeutic role against respiratory ailments.

Background: COVID-19, first reported in China, from the new strain of severe acute respiratory syndrome coronaviruses (SARS-CoV-2), poses a great threat to the world by claiming uncountable lives. SARS-CoV-2 is a highly infectious virus that has been spreading rapidly throughout the world. In the absence of any specific medicine to cure COVID-19, there is an urgent need to develop novel therapeutics, including drug repositioning along with diagnostics and vaccines to combat the COVID-19. Many antivirals, antimalarials, antiparasitic, antibacterials, immunosuppressive anti-inflammatory, and immunoregulatory agents are being clinically investigated for the treatment of COVID-19. Objectives: The earlier developed one parameter regression model correlating the dock scores with in vitro anti-SARS-CoV-2 main protease activity well predicted the six drugs viz remdesivir, chloroquine, favipiravir, ribavirin, penciclovir, and nitazoxanide as potential anti-COVID agents. To further validate our earlier model, the biological activity of nine more recently published SARS-CoV-2 main protease inhibitors has been predicted using our previously reported model. Methods: In the present study, this regression model has been used to screen the existing antiviral, antiparasitic, antitubercular, and anti pneumonia chemotherapeutics utilizing dock score analyses to explore the potential including mechanism of action of these compounds in combating SARS-CoV-2 main protease. Results: The high correlation (R=0.91) explaining 82.3% variance between the experimental versus predicted activities for the nine compounds is observed. It proves the robustness of our developed model. Therefore, this robust model has been further improved, taking a total number of 15 compounds to formulate another model with an R-value of 0.887 and the explained variance of 78.6%. These models have been used for high throughput screening (HTS) of the 21 diverse compounds belonging to antiviral, antiparasitic, antitubercular, and anti pneumonia chemotherapeutics as potential repurpose agents to combat SARS-CoV-2 main protease. The models screened that the drugs bedaquiline and lefamulin have higher binding affinities (dock scores of -8.989 and -9.153 Kcal/mol respectively) than the reference compound {N}-[2-(5-fluoranyl-1~{H}-indol-3-yl)ethyl]ethanamide (dock score of -7.998 Kcal/Mol), as well as higher predicted activities with pEC50 of 0.783 and 0.937 μM and the 0.611 and 0.724 μM respectively. The clinically used repurposed drugs dexamethasone and cefixime have been predicted with pEC50 values of -0.463 and -0.622 μM and -0.311 and -0.428 μM respectively for optimal inhibition. The drugs such as doxycycline, cefpodoxime, ciprofloxacin, sparfloxacin, moxifloxacin, and TBAJ-876 showed moderate binding affinity corresponding to the moderate predicted activity (-1.540 to -1.109 μM). Conclusion: In the present study, validation of our previously developed dock score-based one parametric regression model has been carried out by predicting 9 more SARS-CoV-2 main protease inhibitors. Another model has been formulated to explore the model's robustness. These models have been taken as a barometer for the screening of more potent compounds. The HTS revealed that the drugs such as bedaquiline and lefamulin are highly predicted active compounds, whereas dexamethasone and cefixime have optimal inhibition towards SARS-CoV-2 main protease. The drugs such as doxycycline, cefpodoxime, ciprofloxacin, sparfloxacin, moxifloxacin, and TBAJ-876 have moderately active compounds towards the target inhibition.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic and emergency. Currently, there is no therapeutic agent that has been proven effective against the virus. Objective: We investigated and screened for 401 antiviral compounds that could inhibit one or more of the three protein targets in SARS-CoV-2 chymotrypsin-like (3CL) protease, RNA-dependent RNA polymerase, and spike glycoprotein) using the in-silico approach. Methods: Lipinski’s rule of five was used as an initial screening for relevant compounds. Ligand preparation was conducted using JChem software and Schrödinger’s LigPrep module, while protein elucidation was conducted using AutoDockTools-1.5.6. Molecular docking was analyzed using AutoDockVina. Results: Five antiviral compounds were obtained from each SARS-CoV-2 protein with ideal and potential binding energy as a candidate for target protein inhibition on SARS-CoV-2, TAK-981; lopinavir, mefloquine, and sitagliptin were potent inhibitors of 3CL protease; imatinib, relacatib, AZD7986, imatinib, and TAK-981 proteins showed potential as inhibitors of RdRp tetrandrine, and, selinexor, imatinib, lopinavir, and ciclesonide, showed potential as inhibitors of glycoprotein AZD7986. These compounds have better binding energy than the three comparator drugs, remdesivir, chloroquine, and hydroxychloroquine. Conclusion: We obtained several antiviral compounds with reliable binding energies to the SARSCoV- 2 proteins and potentially better efficacy than the three comparator drugs. Furthermore, this research will help accelerate the development of Covid-19 drugs.

Background: Thiazolepyridine scaffold is considered to be one of the prime constituents of many biologically significant chemical entities. Methods: A set of novel thiazolepyridine derived heterocyclic hybrids, N-phenyl-2-(thiazolo[5,4- b]pyridin-2-yl)benzamides were synthesized by one-pot three-component reaction of 3-aminopyridine-2- thiol, diethyl phthalate, and anilines in a mixture of ethanol and water using HCl as a catalyst. The developed synthetic protocol, which is sustainable and economical, includes the easy work-up procedure, nontoxic, shorter reaction times. This procedure leads to high reaction yields. Results: The synthesized derivatives were screened for their antibacterial activity on Staphylococcus aureus and Bacillus subtilis strains, and 4b,4e, and 4f exhibited moderate bacterial growth inhibition. Similarly, physiochemical properties and different target-based bioactivity scores have been predicted, and almost all the synthesized derivatives scores were found in the accepted range when compared with the standard values. Conclusion: Further structural modifications of the titled compounds would help to understand the structure- activity relations, to design safe and effective lead-like antibacterial agents.

Background: Rituximab represents a drug used for standard Non-Hodgkin’s B-cell lymphoma therapy; however, it displays limited clinical efficacy. Antibody-drug conjugate (ADC) is one of the potential strategies to increase the antitumor activity of an antibody, with improved cytotoxicity directly resulting from the delivery of a molecular warhead. Currently, the warhead monomethyl auristatin E (MMAE) has been widely applied in the study of ADCs, conjugated to a carbamate-based linker (MCVC- PABC). However, the hydrophobic drug-linker (MC-VC-PABC-MMAE) may lead to ADC aggregation, ultimately resulting in decreased activity. Objective: In this study, we developed a hydrophilic drug-linker MC-VC-PABQ-AE linked to rituximab. If the replacement of the tertiary amine in AE for a secondary amine in MMAE represents a characteristic modification, the change of antitumor activity of two corresponding anti-CD20 ADC is unknown, requiring further verification. Methods: The structural elucidation of MC-VC-PAB-AE was displayed by high-resolution mass spectra. The average drug antibody ratio (DAR) of rituximab-VC-AE/MMAE ADCs was performed by HICHPLC. The cell cycle arrest analysis of two ADCs was detected by flow cytometry and the antitumor activity of two ADCs was evaluated in vitro against Ramos and Daudi cells. Results: The average drug antibody ratio (DAR) of two ADCs was approximately 4.0. The activities of rituximab-VC-AE could be increased in CD20 positive B-lymphoma cell lines, most notably due to the higher cell viability inhibitory rates and apoptosis rates compared to rituximab-VC-MMAE. Conclusions: A hydrophilicity linker of ADC was developed and studied. Rituximab-VC-AE may potentially be used against CD20-positive cells, and the therapeutic efficacy and safety bring about further investigations.

Background: Candida albicans is one of the most important causes of fatal fungal infections. Ergosterol, the main sterol in the fungal cell membrane, is the resultant product of Lanosterol in the presence of the enzyme Lanosterolα-demethylase (Cytochrome P450DM). This enzyme is the target enzyme of azole antifungal agents. Aim: To evaluate the antifungal potency of some of the natural compounds via molecular modeling and Absorption, Distribution, Metabolism and Excretion (ADME) study. Methods: The study involved the selection and modeling of the target enzyme, followed by the refinement of the model using molecular dynamic simulation. The modelled structure of the enzyme was validated using the Ramachandran plot and Sequence determination technique. A series of natural compounds was evaluated for cytochrome P450 inhibitory activity using molecular docking studies. The structures of compounds were prepared using a Chem sketch, and molecular docking was performed using Molergo Virtual Docker (MVD) program. Results: The docking study indicated that all the natural compounds have interactivity with protein residue of 14α-demethylase, and the heme prosthetic group and water molecules are present at the active site. The data were also correlated with the synthetic compounds that were experimentally inactive against the fungus and had a low docking score. The compounds with a high dock score were further screened for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profile, and it was predicted that these compounds can be used as lead with a good ADME profile and low toxicity. Conclusion: The natural compound, i.e., curcumin, can easily be used further for lead optimization.