Letters in Drug Design & Discovery - Volume 17, Issue 8, 2020

Background: Novel Coronavirus (COVID-19), respiratory diseases and a major threat to mankind is spreading at an unstoppable rate affecting almost every part of the world with Europe being the most affected continent. Originated from China in December 2019 with sequence homology similar to SARS having a high rate of mutation has created a global pandemic with no effective therapy available. Objective: This editorial summarizes the list of potential antiviral drugs or other effective therapy that is in the clinical trial. Methods: The literature search is based on recent publications (year, 2020) available on PubMed and drug/therapy registered on the ClinicalTrial.gov portal. Results: Hydroxychloroquine, tocilizumab, lopinavir/ritonavir, remdesivir, and convalescent plasma are some of the most common drug/therapy that has come as a hope against COVID-19. Conclusion: In view of the current COVID-19 situation, more rigorous efforts are needed. Drugs with better outcomes need more exploration.

Proteins of B-cell lymphoma (Bcl-2) family are key regulators of apoptosis and are involved in the pathogenesis of various cancers. Disrupting the interactions between the antiapoptotic and proapoptotic Bcl-2 members is an attractive strategy to reactivate the apoptosis of cancer cells. Structure-based drug design (SBDD) has been successfully applied to the discovery of small molecule inhibitors targeting Bcl-2 proteins in past decades. Up to now, many Bcl-2 inhibitors with different paralogue selectivity profiles have been developed and some were used in clinical trials. This review focused on the recent applications of SBDD strategies in the development of small molecule inhibitors targeting Bcl-2 family proteins.

Background: In this work, new heterocyclic compounds containing 3-(4-tertbutylphenyl)- 5-cyclopropyl-4H-1,2,4-triazole ring were synthesized, starting from iminoester hydrochlorides and 4-tert-butylbenzhyrazide. Methods: Ethyl N-[(4-tert-butylphenyl)carbonyl]cyclopropanecarbohydrazonoate was used to synthesize 4-amino-3-(4-tert-butylphenyl)-5-cyclopropyl-4H-1,2,4-triazole, 3-(4-tert-butylphenyl)-5- cyclopropyl-4-(arylmethyleneamino)-4H-1,2,4-triazole, 3-(4-tert-butylphenyl)-5-cyclopropyl-4- (arylmethylamino)-4H-1,2,4-triazole and their phthalonitrile derivatives sequentially. Results: Seventeen new 3-(4-tert-butylphenyl)-5-cyclopropyl-4H-1,2,4-triazole derivatives were synthesized and their antioxidant and antimicrobial activities were determined. Conclusion: Imine and amine derivatives were better antioxidants than phthalonitrile derivatives. Doubly fluorination compounds appeared to result in higher activity. The compounds tested with five microorganisms showed better activity against B. subtilis with the antimicrobial activity of two far exceeding that of ampicillin. Imine and amine derivatives were better antimicrobials than phthalonitrile derivatives.

Background: Acetylcholine deficiency in the hippocampus and cortex, aggregation of amyloid-beta, and beta-secretase overactivity have been introduced as the main reasons in the formation of Alzheimer’s disease. Objective: A new series of cinnamic derived acids linked to 1-benzyl-1,2,3-triazole moiety were designed, synthesized, and evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Methods: Colorimetric Ellman’s method was used for the determination of IC50% of AchE and BuChE inhibitory activity. The kinetic studies, neuroprotective activity, BACE1 inhibitory activity, evaluation of inhibitory potency on Aβ1-42 self-aggregation induced by AchE, and docking study were performed for studying the mechanism of action. Results: Some of the synthesized compounds, compound 7b-4 ((E)-3-(3,4-dimethoxyphenyl)-N-((1- (4-fluorobenzyl)-1H-1,2,3-triazole-4-yl) methyl) acrylamide) depicted the most potent acetylcholinesterase inhibitory activities ( IC50 = 5.27 μM ) and compound 7a-1 (N- ( (1- benzyl- 1H- 1, 2, 3- triazole - 4-yl) methyl) cinnamamide) demonstrated the most potent butyrylcholinesterase inhibitory activities (IC50 = 1.75 μM). Compound 7b-4 showed neuroprotective and β-secretase (BACE1) inhibitory activitiy. In vivo studies of compound 7b-4 in Scopolamine-induced dysfunction confirmed memory improvement. Conclusion: It should be noted that molecular modeling (compounds 7b-4 and 7a-1) and kinetic studies (compounds 7a-1 and 7b-4) showed that these synthesis compounds interacted simultaneously with both the catalytic site (CS) and peripheral anionic site (PAS) of AChE and BuChE.

Background: Kinesins and tubulin inhibitors have attracted researchers’ attention as hopeful targets for achieving effective anticancer agents. Dihydropyrimidine-2-ones (DHPMs) inhibit motor proteins Eg5 in the polymerization process of tubulin, also scaffold bearing benzothiazole heterocycle can block tubulin polymerization/depolymerization. Objective: In this study, the cytotoxic effects and molecular modeling of newly synthesized derivatives of DHPM that were designed by the Scaffold-hopping approach were investigated as potential dual-inhibitors of Eg5 and tubulin. Methods: We investigated the cytotoxic effects of DHPMs derivatives by MTT assay and measureing the Caspase 3 activity. Also, molecular modeling studies were performed by AutoDock4 and GROMACS 4.5.6. Results: According to the results, the d2 derivative (IC50 = 68.58 ± 7, SI = 2.57) eliminates MDA-MB- 231 cells in a dose-dependent manner through caspase-dependent and caspase-independent cell death pathways. Molecular docking studies revealed that the d2 compound could interact with both Eg5 and tubulin key residues. MD simulation also demonstrated the stability of the studied ligand-receptor complexes during the 30 ns of the production run. The effectiveness of substitutions at C4 of the DHPM ring was obtained 4-acetoxy-phenyl, 4-methoxyphenyl, and 4-nitrophenyl, respectively. Conclusion: The findings of the present study provide evidence that DHPM C5 amide derivatives bearing benzothiazole ring might be considered as promising lead compounds for the discovery of novel and multi-target antitumor agents.

Objectives: Trefoil factor family is expressed in several tissues of the body and provides gastric and intestinal protection and healing. This research aims to indicate the mechanism involved in its function. Methods: The intestinal epithelial cells were pretreated with JAK inhibitor AG490 or the concentration of 60ug/ml human recombinant trefoil factor, while the levels of phospho-STAT3, E-cadherin and N-cadherin were detected by Western Blotting. The levels of Matrix Metalloproteinases, Ecadherin and N-cadherin were evaluated by quantitative real time PCR. The cell migration was assessed by the transwell assay and the scratch assay. The immunofluorescence method was performed to detect the reduction of molecular E-cadherin. Results: hTFF3 activates the JAK/STAT3 pathway in HT-29 cells. The effect of JAK/STAT3 pathway mechanism on cell migration promoted by hTFF3. TFF3 promoting cell migration is associated with increased gene transcription of MMPs. hTFF3 alters E-cadherin expression. hTFF3 activates the expression of N-cadherin and down-regulates E-cadherin expression in HT-29 Cells. Conclusion: We have shown that TFF3 activated the JAK/STAT3 pathway. TFF3 increased the level of Matrix Metalloproteinases and N-cadherin, decreased that of E-cadherin, while AG490 had the opposite effect. TFF3 accelerated cell migration and the AG490 relieved the migrating rate to control the levels. TFF3 activated JAK/STAT3 pathway which was associated with intestinal epithelial cell migration.

Background: Protein pharmaceuticals routinely display a series of intrinsic physicochemical instabilities during their production and administration that can unfavorably affect their therapeutic effectiveness. Glycoengineering is one of the most desirable techniques to improve the attributes of therapeutic proteins. One aspect of glycoengineering is the rational manipulation of the peptide backbone to introduce new N-glycosylation consensus sequences (Asn-X-Ser/Thr, where X is any amino acid except proline). Methods: In this work, the amino acid sequence of human chorionic gonadotropin (hCG) was analyzed to identify suitable positions in order to create new N-glycosylation sites. This survey led to the detection of 46 potential N-glycosylation sites. The N-glycosylation probability of all the potential positions was measured with the NetNGlyc 1.0 server. After theoretical reviews and the removal of unsuitable positions, the five acceptable ones were selected for more analyses. Then, threedimensional (3D) structures of the selected analogs were generated and evaluated by SPDBV software. The molecular stability and flexibility profile of five designed analogs were examined using Molecular Dynamics (MD) simulations. Results: Finally, three analogs with one additional N-glycosylation site (V68T, V79N and R67N) were proposed as the qualified analogs that could be glycosylated at the new sites. Conclusion: According to the results of this study, further experimental investigations could be guided on the three analogs. Therefore, our computational strategy can be a valuable method due to the reduction in the number of the expensive, tiresome and time-consuming experimental studies of hCG analogs.

Background: Pyrazolines are reported having anti-inflammatory, anti-oxidant and antidiabetic activities in the literature. Drugs like celecoxib, antipyrine, etc. are structurally similar to the designed compounds. Objectives: To synthesize and characterize N-acetyl pyrazole and quinoline conjugates and test them for Anti-inflammatory, Antioxidant, Antibacterial, Antiamylase and Antimalarial activities. Methods: A series of methoxy substituted quinoline based pyrazoline derivatives (2a-2j) were synthesized in good to excellent yield from corresponding quinoline chalcones (1a-1j). The synthesized compounds were characterized and screened for their in vitro anti-inflammatory, antioxidant, antiamylase, antibacterial and antimalarial activities. Docking and in silico ADMET studies were performed with PDB: 3LN1. Results: Compounds 2b, 2i and 2j showed significant anti-inflammatory activity as compared to standard sodium diclofenac. All compounds (2a-2j) showed excellent antioxidant activity for DPPH even more than standard ascorbic acid. Compounds 2e, 2f, 2h and 2i showed excellent antioxidant activity for NO. as compared to standard ascorbic acid. Compound 2f showed significant antioxidant activity for SOR. Almost all the compounds showed significant antibacterial as well as anti-amylase activity with few exceptions, whereas compounds 2f, 2h and 2j showed potent antimalarial activity. Conclusion: Compounds have shown good anti-inflammatory activities as compared with diclofenac. All the synthesized pyrazoline derivatives showed excellent anti-amylase activity as compared to standard acarbose. Also, compounds have shown good antioxidant antibacterial and antimalarial activities.

Background: Aminoglycoside 6'-N-acetyltransferase type Ib (AAC(6')-Ib) from Klebsiella pneumoniae is an established drug target and has conferred insensitivity to aminoglycosides. Aminoglycosides are often inactivated by aminoglycoside modifying enzymes encoded by genes present in the chromosome, plasmids, and other genetic elements. The AAC(6′)- Ib is an enzyme of clinical importance found in a wide variety of gram-negative pathogens. The AAC(6′)-Ib enzyme is of interest not only because of its ubiquity but also because of other characteristics e.g., it presents significant microheterogeneity at the N-termini and the aac(6′)-Ib gene is often present in integrons, transposons, plasmids, genomic islands, and other genetic structures. The majority of the reported potent inhibitors against the target are substrate analogs. Therefore, there is a need to develop or discover new scaffolds other than substrate analogs as AAC(6')-Ib inhibitor. Objective: The objective of this study is to set optimum parameters for the structure-based virtual screening by multiple docking and scoring methods. The multiple scoring of each ligand also incorporates the ‘Induced Fit’ docking effect that helps to build further confidence in the shortlisted compounds. The method eventually is able to predict the potential inhibitors that bind to the active site and can potentially inhibit the activity of the Aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6’)-Ib] from Klebsiella pneumoniae. Methods: Using the available three-dimensional structure of enzyme AAC(6')-Ib inhibitor complex, a structure-based virtual screening was performed with the hope of prioritizing the promising leads. In order to set up the protocol, 30,000 drug-like molecules were selected from the ChemBridge library. Multiple docking programs, i.e. UCSF DOCK6 and AutoDock Vina have been applied in the current study so that a consensus is developed to the predicted binding modes and thus the docking accuracy. The Amber scores of the Dock6 – a secondary scoring function was also used to perform the ‘Induced Fit’ effect and correspondingly re-rank the compounds. Results: The top 30 ranked compounds of the most frequent scored were selected from the histogram. The 2D interactions of those 30 compounds were drawn from the Ligplot+ tool. Six of the compounds were prioritized as potential inhibitors as they are representing the maximum number of interactions from the rest of the compounds and also possess the drug-likeness as predicted by the estimated ADMET properties. Conclusion: This study provided useful insight that the proposed compounds have the potential to bind to the aminoglycoside binding site of AAC(6′)-Ib that may eventually inhibit the Klebsiella pneumoniae. This study has the potential to propose putative new and novel inhibitors against a resistant drug target of Klebsiella pneumoniae.

Background: In this study, modulators of human Chemotactic cytokine receptor 5 (CCR5) were described using a quantitative structure-activity relationship model (QSAR). This model was based on the molecule’s chemical structure. Methods: All 56 compounds of CCR5 receptor antagonists were randomly separated into two sets, 43 were reserved for training and the other 13 for testing. In the course of this study, molecular models were drawn using ChemDraw software. By means of Hyperchem software as well as optimized with both AM1 (semi-empirical self-consistent-field molecular orbital) and MM+ (molecular mechanics plus force field), molecular models were described through numerous descriptors using CODESSA software. Results: Linear models were obtained by Heuristic Method (HM) software and nonlinear models were obtained using APS software with optimal descriptor combinations used to build linear QSAR models, involving a group of selected descriptors. As a result, values of the above two different sets were shown to result from 0.82 in testing and 0.86 in training in HM while 0.83 in testing and 0.88 in training in Gene Expression Programming (GEP). Conclusion: From this method, the activity of molecules could be predicted, and the molecular structure could be changed to alter its IC50, avoiding the testing of large numbers of compounds.

Background: Antimicrobial Resistance (AMR) and Tuberculosis (TB) are global concern. According to the WHO fact sheet on tuberculosis, in 2017, 10 million people fell ill with TB, and 1.6 million including 230,000 children died from the disease. There is a critical need of design and development of novel chemotherapeutic agents to combat the emergence and increasing prevalence of resistant pathogens. In the present study, a new series of 1,3,4-oxadiazoles incorporating benzimidazole and pyridine scaffolds in a single molecular framework has been reported. Methods: The structures of the synthesized derivatives (4a to 4e) were assigned by IR, NMR and mass spectral techniques. The hybrid compounds were evaluated for their antimicrobial, antitubercular and antioxidant activities. In addition, docking simulations were performed to study ligand-protein interactions and to determine the probable binding conformations. Results: Molecule 4a has shown anti-tubular activities with MIC 1.6 μg/ml. As compared to ascorbic acid activities (IC50 = 62.91 μg/ml), molecule 4e exhibited better antioxidant activities (IC50 = 24.85 μg/ml). Also, molecule 4e has shown significant antimicrobial activities. Conclusion: The synthesized derivatives from 4a to 4e have exhibited various medicinal activities and could be emerged as lead compounds and further explored as potential therapeutic agents.

Background: MDA-MB-231 is a Triple-Negative Breast Cancer (TNBC) cell line, which is resistant to tyrosine kinase inhibitors, such as lapatinib. Lapatinib is well-recognized as an anti- EGFR and anti-Her2 compound. Here, we report one of the possible explanations for lapatinibresistance in TNBC cells, the most incurable type of breast cancer. Methods: Using western blotting, we have observed that lapatinib-treated cells enhanced activation of Akt, an oncogenic protein activated at downstream of EGFR signaling. Results: Anti-EGFR activity of Lapatinib would be counteracted with sustained activation of Akt. We found lapatinib-resistance in TNBC can be managed by administering Akt inhibitors. Further, lapatinib enhanced PI3K/Akt signaling is an alternative pathway to ensure the viability of MDAMB- 231 cells. There might also be unknown targets for lapatinib, which needs further investigation. Conclusion: This observation opens up a new discussion on overcoming resistance to tyrosine kinase inhibitors, a key challenge in treating TNBC.