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Molecules (Basel, Switzerland) Nov 2020Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is...
Wuhan, China was the epicenter of the first zoonotic transmission of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) in December 2019 and it is the causative agent of the novel human coronavirus disease 2019 (COVID-19). Almost from the beginning of the COVID-19 outbreak several attempts were made to predict possible drugs capable of inhibiting the virus replication. In the present work a drug repurposing study is performed to identify potential SARS-CoV-2 protease inhibitors. We created a Quantitative Structure-Activity Relationship (QSAR) model based on a machine learning strategy using hundreds of inhibitor molecules of the main protease (M) of the SARS-CoV coronavirus. The QSAR model was used for virtual screening of a large list of drugs from the DrugBank database. The best 20 candidates were then evaluated in-silico against the M of SARS-CoV-2 by using docking and molecular dynamics analyses. Docking was done by using the Gold software, and the free energies of binding were predicted with the MM-PBSA method as implemented in AMBER. Our results indicate that levothyroxine, amobarbital and ABP-700 are the best potential inhibitors of the SARS-CoV-2 virus through their binding to the M enzyme. Five other compounds showed also a negative but small free energy of binding: nikethamide, nifurtimox, rebimastat, apomine and rebastinib.
Topics: Amobarbital; Antiviral Agents; Binding Sites; Computer Simulation; Coronavirus 3C Proteases; Drug Discovery; Drug Repositioning; Humans; Machine Learning; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Protease Inhibitors; Protein Binding; Quantitative Structure-Activity Relationship; SARS-CoV-2; Small Molecule Libraries; Software; Thermodynamics; Thyroxine; COVID-19 Drug Treatment
PubMed: 33172092
DOI: 10.3390/molecules25215172 -
Bioorganic & Medicinal Chemistry Jul 2020HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering...
HMG-CoA reductase (HMGCR) is a rate-limiting enzyme in the cholesterol biosynthetic pathway, and its catalytic domain is the well-known target of cholesterol-lowering drugs, statins. HMGCR is subject to layers of negative feedback loops; excess cholesterol inhibits transcription of the gene, and lanosterols and oxysterols accelerate degradation of HMGCR. A class of synthetic small molecules, bisphosphonate esters exemplified by SR12813, has been known to induce accelerated degradation of HMGCR and reduce the serum cholesterol level. Although genetic and biochemical studies revealed that the accelerated degradation requires the membrane domain of HMGCR and Insig, an oxysterol sensor on the endoplasmic reticulum membrane, the direct target of the bisphosphonate esters remains unclear. In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure-activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme.
Topics: Cells, Cultured; Diphosphonates; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Molecular Structure; Structure-Activity Relationship
PubMed: 32616181
DOI: 10.1016/j.bmc.2020.115576 -
Drug Design, Development and Therapy 2016Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To...
Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To identify the optimum antioxidant agent/combination for apomorphine solution, a high performance liquid chromatography assay was used to study the stability of 50 μg/mL apomorphine HCI in 0.1% L-ascorbic acid (AA), 0.1% sodium metabisulfite (SMB), 0.1% EDTA, and in selected combinations at 25°C, 32°C, and 37°C over a period of 14 days. The stability of apomorphine HCl (10 mg/mL) in 0.1% AA solution and in 0.1% EDTA solution at 25°C and 37°C was also evaluated. Apomorphine HCI solution (50 μg/mL) in 0.1% AA plus 0.1% SMB solution retained 99.7% (at 25°C) and 95.9% (at 37°C) of the initial concentration, as 0.1% AA plus SMB solution minimized the reactive oxygen content in solution which, in turn, reduced the oxidation rate of apomorphine HCl, and there was no green coloration perceptible. Conversely, apomorphine HCl solution (50 μg/mL) in 0.1% SMB solution was unstable as only 0.53% (at 25°C) and 0.06% (at 37°C) of the initial concentration was retained after 14 days. All 10 mg/mL apomorphine HCl samples were stable in both studies. The initial concentration of apomorphine HCl solution markedly affected its rate of oxidation and discoloration. The addition of 0.1% AA to a current formulation of apomorphine HCl injection (Apomine), which contains SMB as an antioxidant, was recommended as providing the most stable solution.
Topics: Antioxidants; Apomorphine; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Drug Stability; Mass Spectrometry; Oxidation-Reduction
PubMed: 27757015
DOI: 10.2147/DDDT.S116848 -
Cancer Feb 2012Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and...
BACKGROUND
Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis.
METHODS
The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines.
RESULTS
Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used.
CONCLUSIONS
The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bone Neoplasms; Cell Cycle; Cell Proliferation; Diphosphonates; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Male; Mice; Mice, Inbred C3H; Osteosarcoma; Protein Prenylation; Rats; Tumor Cells, Cultured
PubMed: 21751201
DOI: 10.1002/cncr.26336 -
International Journal of Pharmaceutics Dec 2009Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy....
Apomine is a novel compound that inhibits the mevalonate/isoprenoid pathway of cholesterol synthesis and may prove effective as a skin cancer chemoprevention therapy. This research was focused on the development of a new delivery approach for chemoprevention of melanoma using topically delivered apomine. This included evaluating the effect of several factors on the stability of apomine in solution, utilizing these to develop a topical formulation, and conducting efficacy studies with the developed topical formulation in the TPras mouse model. Preformulation included the influence of pH, buffer species, ionic strength, and organic solvents on the stability of apomine at four different temperatures. Apomine was determined to undergo apparent first-order degradation kinetics for all conditions evaluated. Apomine undergoes base-catalyzed degradation. Less than 15% degradation is observed after >200 days under acidic conditions. Long-term stability studies were performed on two different topical cream formulations and indicate that both formulations are chemically stable for over 1 year at both 4 and 23 degrees C. The efficacy of topically applied apomine, from ethanol and developed 1% cream, was evaluated in vivo against the incidence of melanoma. Regardless of delivery vehicle apomine treatment caused a significant reduction in tumor incidence. Ethyl alcohol application of apomine resulted in a greater tumor incidence reduction when compared to the development cream formulation; however, this difference was not significant.
Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Topical; Animals; Anticarcinogenic Agents; Buffers; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Diphosphonates; Drug Stability; Ethanol; Hydrogen-Ion Concentration; Kinetics; Melanoma, Experimental; Mice; Ointments; Osmolar Concentration; Skin Neoplasms; Solubility; Solvents; Technology, Pharmaceutical; Temperature; ras Proteins
PubMed: 19699284
DOI: 10.1016/j.ijpharm.2009.08.016 -
The Journal of Pharmacology and... Jul 2007Apomine, a 1,1-bisphosphonate-ester with antitumor activity, has previously been reported to strongly down-regulate 3-hydroxy-3-methylglutaryl-coenzyme A reductase...
Apomine, a 1,1-bisphosphonate-ester with antitumor activity, has previously been reported to strongly down-regulate 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in the mevalonate pathway responsible for the prenylation of proteins. Here, we show that although apomine down-regulated HMG-CoA reductase protein levels in myeloma cells, it did not inhibit protein prenylation, and apomine-induced apoptosis could not be prevented by mevalonate, indicating that apomine cytotoxicity is independent from its effects on HMG-CoA reductase. Instead, apomine cytotoxicity was prevented by the addition of phosphatidylcholine, which is similar to the previously reported ability of phosphatidylcholine to overcome the cytotoxicity of farnesol, whereas phosphatidylcholine had no effect on down-regulation of HMG-CoA reductase by apomine. These findings raised the possibility that apomine, independent from its own cytotoxic effects, could enhance the antitumor effects of the competitive HMG-CoA reductase inhibitor lovastatin via down-regulating HMG-CoA reductase. Indeed, treatment with apomine in combination with lovastatin resulted in synergistic decreases in viable cell number and induction of apoptosis. At the concentrations used, apomine down-regulated HMG-CoA reductase protein levels without being cytotoxic. Accumulation of unprenylated Rap1A by lovastatin was enhanced in the presence of apomine. Furthermore, synergy was completely prevented by mevalonate, and apomine did not synergize with desoxolovastatin, which does not inhibit HMG-CoA reductase. We conclude that the synergistic drug interaction results from an enhancement by apomine of the effects of lovastatin, mediated by down-regulation of HMG-CoA reductase by apomine. Thus, these findings demonstrate a novel strategy for enhancing the antitumor effects of lovastatin.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Diphosphonates; Down-Regulation; Drug Synergism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mevalonic Acid; Multiple Myeloma; Phosphatidylcholines; Protein Prenylation
PubMed: 17412884
DOI: 10.1124/jpet.106.116467 -
International Journal of Cancer Apr 2007Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol...
Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease.
Topics: Animals; Apoptosis; Bone Density; Bone Resorption; Diphosphonates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Multiple Myeloma; Osteoclasts; Paraproteins; Tumor Cells, Cultured
PubMed: 17230522
DOI: 10.1002/ijc.22478 -
Investigational New Drugs Apr 2007Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well...
Apomine, a novel bisphosphonate ester, has demonstrated anticancer activity in a variety of cancer cell lines; however, its mechanism of cytotoxicity is not well understood. Previous work has demonstrated that Apomine induces cell death by activation of caspase-3 in several cancer cell types. However, we have demonstrated that Apomine induces cell death in the A375 human melanoma cell line through a novel membrane-mediated mechanism that is independent of caspase-3 activation. This mechanism of membrane lysis may apply to other bisphosphonates and may be an important mechanism for overcoming resistance to apoptosis. Interestingly, Apomine-mediated cell death in the A375 and UACC 3093 human melanoma cell lines is also independent of N-Ras farnesylation, which was a previously described mechanism of action for Apomine in other cancer cell types. These data suggest that Apomine induces cell death through a novel plasma membrane-mediated cytolytic pathway, independent of caspase-3 activation and N-Ras farnesylation.
Topics: Antineoplastic Agents; Apoptosis; Caspases; Cell Line, Tumor; Cell Membrane; Cell Survival; Cytosol; DNA, Neoplasm; Diphosphonates; Enzyme Activation; Genes, ras; Humans; Immunoblotting; L-Lactate Dehydrogenase; Melanoma; Poly(ADP-ribose) Polymerases; Thymidine; ras Proteins
PubMed: 17024575
DOI: 10.1007/s10637-006-9015-6 -
Methods and Findings in Experimental... Sep 2006Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved... (Review)
Review
Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com This issue focuses on the following selection of drugs: A-007, A6, adalimumab, adenosine triphosphate, alefacept, alemtuzumab, AllerVax Ragweed, amphora, anakinra, angiotensin-(1-7), anidulafungin, apomine, aripiprazole, atomoxetine hydrochloride, avanafil; BAL-8557, becatecarin, bevacizumab, biphasic insulin aspart, BMS-188797, bortezomib, bosentan, botulinum toxin type B, brivudine; Calcipotriol/betamethasone dipropionate, caspofungin acetate, catumaxomab, certolizumab pegol, cetuximab, CG-0070, ciclesonide, cinacalcet hydrochloride, clindamycin phosphate/benzoyl peroxide, cryptophycin 52, Cypher; Dabigatran etexilate, darapladib, darbepoetin alfa, decitabine, deferasirox, desloratadine, dexanabinol, dextromethorphan/quinidine sulfate, DMF, drotrecogin alfa (activated), duloxetine hydrochloride; E-7010, edaravone, efalizumab, emtricitabine, entecavir, eplerenone, erlotinib hydrochloride, escitalopram oxalate, estradiol valerate/dienogest, eszopiclone, exenatide, ezetimibe; Fondaparinux sodium, fulvestrant; Gefitinib, gestodene, GYKI-16084; Hyaluronic acid, hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, indiplon, insulin glargine; Juzen-taiho-to; Lamivudine/zidovudine/abacavir sulfate, L-arginine hydrochloride, lasofoxifene tartrate, L-BLP-25, lenalidomide, levocetirizine, levodopa/carbidopa/entacapone, lexatumumab, lidocaine/prilocaine, lubiprostone, lumiracoxib; MAb-14.18, mitoquidone; Natalizumab, neridronic acid, neuradiab; Olpadronic acid sodium salt, omalizumab; p53-DC vaccine, parathyroid hormone (human recombinant), peginterferon alfa-2a, peginterferon alfa-2b, pemetrexed disodium, perifosine, pimecrolimus, prasterone, prasugrel, PRO-2000, Pseudostat; R24, rasburicase, RHAMM R3 peptide, rilonacept, rosuvastatin calcium, rotavirus vaccine, rufinamide; Sabarubicin hydrochloride, SHL-749, sirolimus-eluting stent, SLx-2101, sodium butyrate, sorafenib, SU-6668; TachoSil, tadalafil, taxus, tegaserod maleate, telbivudine, tenofovir disoproxil fumarate, teriparatide, tetramethylpyrazine, teverelix, tiotropium bromide, tipifarnib, tirapazamine, tolvaptan, TransvaxTM hepatitis C vaccine, treprostinil sodium; Valganciclovir hydrochloride, valsartan/amlodipine, vandetanib, vardenafil hydrochloride hydrate, vatalanib succinate, veglin, voriconazole; Yttrium 90 (90Y) ibritumomab tiuxetan; Zileuton, zotarolimus, zotarolimus-eluting stent.
Topics: Clinical Trials as Topic; Combined Modality Therapy; Drug Therapy; Humans; Treatment Outcome
PubMed: 17003851
DOI: No ID Found -
Investigational New Drugs Jan 2006Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective...
Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphosphonates; Female; Humans; Male; Melanoma; Middle Aged
PubMed: 16379038
DOI: 10.1007/s10637-005-4544-y