Abstract: The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (M(pro)) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 M(pro) as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of M(pro) by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among M(pro) of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 M(pro) active site and also offers direction for further lead optimization and rational drug design.

Abstract: SARS-CoV-2 has devastated the world with its rapid spread and fatality. The researchers across the globe are struggling hard to search a drug to treat this infection. Understanding the time constraint, the best approach is to study clinically approved drugs for control of this deadly pandemic of COVID 19. The repurposing of such drugs can be supported with the study of molecular interactions to enhance the possibility of application. The present work is a molecular docking study of proteins responsible for viral propagation namely 3Clpro, Nsp10/16, Spike protein, SARS protein receptor binding domain, Nsp 9 viral single strand binding protein and viral helicase. The protein through virus enters the host cell-human angiotensin-converting enzyme 2 (ACE2) receptor, is also used as a target for molecular docking. The docking was done with most discussed drugs for SARS-CoV-2 like Ritonavir, Lopinavir, Remdesivir, Chloroquine, Hydroxychloroquine (HCQ), routine antiviral drugs like Oseltamivir and Ribavirin. In addition, small molecules with anti-inflammatory actions like Mycophenolic acid (MPA), Pemirolast, Isoniazid and Eriodictyol were also tested. The generated data confirms the potential of Ritonavir, Lopinavir and Remdesivir as a therapeutic candidate against SARS-CoV-2. It is observed that Eriodictyol binds to almost all selected target proteins with good binding energy, suggesting its importance in treatment of COVID 19. Molecular interactions of Ritonavir, Lopinavir and Remdesivir against SARS-CoV-2 proteins enhanced their potential as a candidate drug for treatment of COVID-19. Eriodictyol had emerged as a new repurposing drug that can be used in COVID-19.

Abstract: BACKGROUND: Evidence concerning the potential repurposing of antihypertensives for Alzheimer's disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer's disease. METHODS: We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer's disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer's disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets. RESULTS: There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer's disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153). CONCLUSIONS: Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer's disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer's disease, they may not do so via systolic blood pressure.

Abstract: OBJECTIVE: To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening. METHODS: The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper. RESULTS: It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score. CONCLUSIONS: A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

Abstract: The deregulated genes in colorectal cancer (CRC) vary significantly across different studies. Thus, a systems biology approach is needed to identify the co-deregulated genes (co-DEGs), explore their molecular networks, and spot the major hub proteins within these networks. We reanalyzed 19 GEO gene expression profiles to identify and annotate CRC versus normal signatures, single-gene perturbation, and single-drug perturbation signatures. We identified the co-DEGs across different studies, their upstream regulating kinases and transcription factors (TFs). Connectivity Map was used to identify likely repurposing drugs against CRC within each group. The functional changes of the co-upregulated genes in the first category were mainly associated with negative regulation of transforming growth factor beta production and glomerular epithelial cell differentiation; whereas the co-downregulated genes were enriched in cotranslational protein targeting to the membrane. We identified 17 hub proteins across the co-upregulated genes and 18 hub proteins across the co-downregulated genes, composed of well-known TFs (MYC, TCF3, PML) and kinases (CSNK2A1, CDK1/4, MAPK14), and validated most of them using GEPIA2 and HPA, but also through two signature gene lists composed of the co-up and co-downregulated genes. We further identified a list of repurposing drugs that can potentially target the co-DEGs in CRC, including camptothecin, neostigmine bromide, emetine, remoxipride, cephaeline, thioridazine, and omeprazole. Similar analyses were performed in the co-DEG signatures in single-gene or drug perturbation experiments in CRC. MYC, PML, CDKs, CSNK2A1, and MAPKs were common hub proteins among all studies. Overall, we identified the critical genes in CRC and we propose repurposing drugs that could be used against them.

Abstract: INTRODUCTION: Most adults with type 2 diabetes (T2D) have several chronic conditions treated with complex regimens and multiple medications. The burden and complexity of multiple medication use are associated with worse patient outcomes, including reduced adherence and increased costs, hospitalizations, mortality rates, and HbA1c. This study quantifies the chronic medication burden, regimen complexity, and potential medication interactions in patients with T2D using a nationwide claims database in the USA. METHODS: Adults with T2D treated for greater than half of the year with at least one glucose-lowering agent (GLA) in 2017 were included in this descriptive study. Chronic medications were defined as all GLAs and non-GLA medications prescribed for at least 90 days in 2017 to at least 2% of the cohort. Medication burden, defined as the number of medications prescribed, was examined. Medication complexity, proxied by the Medication Regimen Complexity Index (MRCI), and potential use of interacting medications were also examined. Results were investigated for all chronic medications and were reported on the basis of the disease treated (diabetes or other condition) and the route of administration (oral or other). RESULTS: On average, in 2017, the 814,156 patients included in the study filled prescriptions for 4.1 chronic medications (standard deviation [SD] = 2.0), 3.7 oral chronic medications (SD = 1.9), 1.5 GLAs (SD = 0.8), and 1.1 oral GLAs (SD = 0.7). The average MRCI was 14.7 for all chronic medications (SD = 7.4), with a mean of 12.4 for all oral chronic medications (SD = 6.3), 6.6 for all GLAs (SD = 3.8), and 4.9 for oral GLAs (SD = 2.6). CONCLUSION: On average, patients with T2D used multiple medications, had a complex medication regimen, and were at potential risk of medication interactions. These findings suggest that patients, practitioners, pharmacists, and payers may benefit from interventions which decrease medication burden, complexity, and/or adverse events related to the treatment of T2D.

Abstract: The COVID-19 pandemic caused by SARS-CoV-2 has is a global health challenge. Angiotensin-converting enzyme 2 (ACE2) is the host receptor for SARS-CoV-2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEIs) or angiotensin receptor blockers have a higher risk of COVID-19 infection as these drugs could upregulate ACE2, motivating the study of ACE2 modulation by drugs in current clinical use. Here, we mined published datasets to determine the effects of hundreds of clinically approved drugs on ACE2 expression. We find that ACEIs are enriched for ACE2-upregulating drugs, while antineoplastic agents are enriched for ACE2-downregulating drugs. Vorinostat and isotretinoin are the top ACE2 up/downregulators, respectively, in cell lines. Dexamethasone, a corticosteroid used in treating severe acute respiratory syndrome and COVID-19, significantly upregulates ACE2 both in vitro and in vivo. Further top ACE2 regulators in vivo or in primary cells include erlotinib and bleomycin in the lung and vancomycin, cisplatin, and probenecid in the kidney. Our study provides leads for future work studying ACE2 expression modulators.

Abstract: Background: Since anaplastic thyroid carcinoma (ATC) has rapid progression and a poor outcome, identification of the key genes and underlying mechanisms of ATC is required. Methods: Gene expression profiles of GSE29265 and GSE33630 were available from the Gene Expression Omnibus database. The two profile datasets included 19 ATC tissues, 55 normal thyroid tissues and 59 papillary thyroid cancer (PTC) tissues. Differentially expressed genes (DEGs) between ATC tissues and normal thyroid tissues as well as ATC tissues and PTC tissues were identified using the GEO2R tool. Common DEGs between the two datasets were selected via Venn software online. Then, we applied the Database for Annotation, Visualization and Integrated Discovery for Kyoto Encyclopedia of Gene and Genome pathway and gene ontology (GO) analyses. Additionally, protein-protein interactions (PPIs) of these DEGs were visualized via Cytoscape with Search Tool for the Retrieval of Interacting Genes. In the PPI networks analyzed by the Molecular Complex Detection plug-in, all 54 upregulated core genes were selected. Furthermore, Kaplan-Meier analysis was applied to analyze overall survival based on these 54 genes. Then, we used the DrugBank database to identify drug relationships for the 54 genes. Additionally, we validated the correlations between genes enriched in pathways and genes identified as prognosis biomarkers of THCA by Gene Expression Profiling Interactive Analysis. Results: Four genes (CCNB1, CCNB2, CDK1 and CHEK1) involved cell cycle arrest and DNA repair were significantly enriched in the G2/M phase of the cell cycle pathway and before G2 phase arrest of the P53 pathway. Inhibitors of CHEK1, CDK1 and TOP2A were identified in the DrugBank database. ANLN, DEPDC1, KIF2C, CENPN, TACC3 CCNB2 and CDC6 were hypothesized to be prognostic biomarkers of ATC. Furthermore, CCNB1, CCNB2, CDK1 and CHEK1 were significantly positively associated with these prognosis genes. Conclusions: CCNB1, CCNB2, CDK1 and CHEK1 may be key genes involved cell cycle arrest and DNA damage repair in ATC. Further studies are required to confirm the contributions of the identified genes to ATC progression and survival.

Abstract: BACKGROUND: So far only trastuzumab, pembrolizumab and ramucirumab have been approved by the FDA for targeted therapy in gastric cancer (GC). Here we report on potential targeted therapy options for gastric adenocarcinoma based on a novel analysis of "The Cancer Genome Atlas (TCGA)" database. METHODS: One hundred two FDA-approved targeted cancer drugs were compiled and molecular targets defined. Drugs were considered as potentially effective if targeted genes showed (1) an increase in copy number, (2) gain of function with oncogene activation, (3) specific alterations responsive to approved drugs. Additionally, genetic changes that confer drug resistance and/or sensitivity were evaluated. RESULTS: Fifty percentage of patients with GC may be treatable with non-GC but FDA-approved targeted cancer therapies. The major drug identified in our in silico study for GC is copanlisib, a PI3K inhibitor. In the TCGA patient database, our genetically based drug response prediction identified more patients with alterations sensitive to copanlisib compared to the already-GC-approved drug trastuzumab (20%, 78 out of 393 patients, vs. trastuzumab: 13%, 52 of 393 patients), which is mainly due to the high incidence of PIK3CA gain of function mutations within mutation hot spots. CONCLUSION: Our results demonstrate that various currently FDA-approved drugs might be candidates for targeted therapy of GC. For clinical trials, cancer patients should be selected based on the genomic profile of their tumor.

Abstract: OBJECTIVE: Yohimbine pharmacokinetics were determined after oral administration of a single oral dose of yohimbine 5 mg and a microdose of yohimbine 50 microg in relation to different cytochrome P450 (CYP) 2D6 genotypes. The CYP2D6 inhibitor paroxetine was used to investigate the influence on yohimbine pharmacokinetics. Microdosed midazolam was applied to evaluate a possible impact of yohimbine on CYP3A activity and the possibility of combining microdosed yohimbine and midazolam to simultaneously determine CYP2D6 and CYP3A activity. METHODS: In a fixed-sequence clinical trial, 16 healthy volunteers with a known CYP2D6 genotype [extensive (10), intermediate (2) and poor (4) metaboliser] received an oral dose of yohimbine 50 microg, yohimbine 5 mg at baseline and during paroxetine as a CYP2D6 inhibitor. Midazolam (30 microg) was co-administered to determine CYP3A activity at each occasion. Plasma concentrations of yohimbine, its main metabolite 11-OH-yohimbine, midazolam and paroxetine were quantified using validated liquid chromatography-tandem mass spectrometry assays. RESULTS: Pharmacokinetics of yohimbine were highly variable and a CYP2D6 genotype dependent clearance was observed. After yohimbine 5 mg, the clearance ranged from 25.3 to 15,864 mL/min and after yohimbine 50 microg, the clearance ranged from 39.6 to 38,822 mL/min. A more than fivefold reduction in clearance was caused by paroxetine in CYP2D6 extensive metabolisers, while the clearance in poor metabolisers was not affected. Yohimbine did not alter CYP3A activity as measured by microdosed midazolam. CONCLUSIONS: The pharmacokinetics of yohimbine were highly correlated with CYP2D6, which was further supported by the clearance inhibition caused by the CYP2D6 inhibitor paroxetine. With these data, yohimbine is proposed to be a suitable probe drug to predict CYP2D6 activity. In addition, the microdose can be used in combination with microdosed midazolam to simultaneously evaluate CYP2D6 and CYP3A activity without any interaction between the probe drugs and because the microdoses exert no pharmacological effects. CLINICAL TRIAL REGISTRATION: EudraCT2017-001801-34.