Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 98
Filter
1.
J Comput Chem ; 45(5): 247-263, 2024 Feb 15.
Article in English | MEDLINE | ID: mdl-37787086

ABSTRACT

At the beginning of the last century, multiple pandemics caused by influenza (flu) viruses severely impacted public health. Despite the development of vaccinations and antiviral medications to prevent and control impending flu outbreaks, unforeseen novel strains and continuously evolving old strains continue to represent a serious threat to human life. Therefore, the recently identified H10N7, for which not much data is available for rational structure-based drug design, needs to be further explored. Here, we investigated the structural dynamics of neuraminidase N7 upon binding of inhibitors, and the drug resistance mechanisms against the oseltamivir (OTV) and laninamivir (LNV) antivirals due to the crucial R292K mutation on the N7 using the computational microscope, molecular dynamics (MD) simulations. In this study, each system underwent long 2 × 1 µs MD simulations to answer the conformational changes and drug resistance mechanisms. These long time-scale dynamics simulations and free energy landscapes demonstrated that the mutant systems showed a high degree of conformational variation compared to their wildtype (WT) counterparts, and the LNV-bound mutant exhibited an extended 150-loop conformation. Further, the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculation and MM/GBSA free energy decomposition were used to characterize the binding of OTV and LNV with WT, and R292K mutated N7, revealing the R292K mutation as drug-resistant, facilitated by a decline in binding interaction and a reduction in the dehydration penalty. Due to the broader binding pocket cavity of the smaller K292 mutant residue relative to the wildtype, the drug carboxylate to K292 hydrogen bonding was lost, and the area surrounding the K292 residue was more accessible to water molecules. This implies that drug resistance could be reduced by strengthening the hydrogen bond contacts between N7 inhibitors and altered N7, creating inhibitors that can form a hydrogen bond to the mutant K292, or preserving the closed cavity conformations.


Subject(s)
Influenza A Virus, H10N7 Subtype , Influenza, Human , Humans , Influenza, Human/drug therapy , Antiviral Agents/pharmacology , Neuraminidase/chemistry , Drug Resistance, Viral/genetics , Oseltamivir/pharmacology , Oseltamivir/chemistry , Oseltamivir/metabolism , Mutation , Molecular Dynamics Simulation , Enzyme Inhibitors/pharmacology
2.
Geroscience ; 45(3): 1539-1555, 2023 06.
Article in English | MEDLINE | ID: mdl-36867284

ABSTRACT

Terminal sialic acid residues are present on most glycoproteins and glycolipids, but levels of sialylation are known to change in the brain throughout the lifespan as well as during disease. Sialic acids are important for numerous cellular processes including cell adhesion, neurodevelopment, and immune regulation as well as pathogen invasion into host cells. Neuraminidase enzymes, also known as sialidases, are responsible for removal of terminal sialic acids in a process known as desialylation. Neuraminidase 1 (Neu1) cleaves the α-2,6 bond of terminal sialic acids. Aging individuals with dementia are often treated with the antiviral medication oseltamivir, which is associated with induction of adverse neuropsychiatric side effects; this drug inhibits both viral and mammalian Neu1. The present study tested whether a clinically relevant antiviral dosing regimen of oseltamivir would disrupt behavior in the 5XFAD mouse model of Alzheimer's disease amyloid pathology or wild-type littermates. While oseltamivir treatment did not impact mouse behavior or modify amyloid plaque size or morphology, a novel spatial distribution of α-2,6 sialic acid residues was discovered in 5XFAD mice that was not present in wild-type littermates. Further analyses revealed that α-2,6 sialic acid residues were not localized the amyloid plaques but instead localized to plaque-associated microglia. Notably, treatment with oseltamivir did not alter α-2,6 sialic acid distribution on plaque-associated microglia in 5XFAD mice which may be due to downregulation of Neu1 transcript levels in 5XFAD mice. Overall, this study suggests that plaque-associated microglia are highly sialylated and are resistant to change with oseltamivir, thus interfering with microglia immune recognition of and response to amyloid pathology.


Subject(s)
Microglia , N-Acetylneuraminic Acid , Mice , Animals , N-Acetylneuraminic Acid/metabolism , N-Acetylneuraminic Acid/pharmacology , Oseltamivir/pharmacology , Oseltamivir/metabolism , Neuraminidase/metabolism , Neuraminidase/pharmacology , Sialic Acids/metabolism , Sialic Acids/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/metabolism , Mammals
3.
Biotechnol Adv ; 62: 108073, 2023.
Article in English | MEDLINE | ID: mdl-36464143

ABSTRACT

Shikimic acid (SA), a hydroaromatic natural product, is used as a chiral precursor for organic synthesis of oseltamivir (Tamiflu®, an antiviral drug). The process of microbial production of SA has recently undergone vigorous development. Particularly, the sustainable construction of recombinant Corynebacterium glutamicum (141.2 g/L) and Escherichia coli (87 g/L) laid a solid foundation for the microbial fermentation production of SA. However, its industrial application is restricted by limitations such as the lack of fermentation tests for industrial-scale and the requirement of growth-limiting factors, antibiotics, and inducers. Therefore, the development of SA biosensors and dynamic molecular switches, as well as genetic modification strategies and optimization of the fermentation process based on omics technology could improve the performance of SA-producing strains. In this review, recent advances in the development of SA-producing strains, including genetic modification strategies, metabolic pathway construction, and biosensor-assisted evolution, are discussed and critically reviewed. Finally, future challenges and perspectives for further reinforcing the development of robust SA-producing strains are predicted, providing theoretical guidance for the industrial production of SA.


Subject(s)
Escherichia coli , Shikimic Acid , Shikimic Acid/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Oseltamivir/metabolism , Antiviral Agents , Fermentation , Metabolic Engineering
4.
Bioorg Chem ; 129: 106118, 2022 12.
Article in English | MEDLINE | ID: mdl-36067538

ABSTRACT

Triptolide (TP) is a major active compound derived from the traditional Chinese medicine Tripterygium wilfordii. TP has been reported to inhibit the infection of HIV and a few other viruses. However, the antiviral spectrum and the underlying mechanisms of TP are incompletely defined. TP derivatives were designed, synthesized, and evaluated for anti-influenza activity against the influenza A virus in this study. All of them exhibited activities against oseltamivir sensitive influenza A/WSN/33 virus (H1N1) and oseltamivir resistant influenza A/PR/8/33 virus (H1N1) with low cytotoxicity in vitro. In our present study, TP derivatives probably suppressed influenza virus replication through inhibiting ribonucleoprotein complex nucleus export of influenza A virus by binding with viral nucleoprotein. Moreover, TP derivatives downregulated influenza A virus-induced macrophage cytokine storm in a dose-dependent manner, through inhibiting nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome signaling. Taken together, TP derivatives suppressed influenza A virus replication by directly targeting NP and regulating innate immune responses induced by influenza A virus infection, which suggested that TP derivatives might be prospective candidates for potent antivirals.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza A virus , Influenza, Human , Humans , Nucleoproteins/chemistry , Nucleoproteins/metabolism , Oseltamivir/metabolism , Influenza, Human/drug therapy , Antiviral Agents/chemistry
5.
PLoS Comput Biol ; 18(7): e1010343, 2022 07.
Article in English | MEDLINE | ID: mdl-35901128

ABSTRACT

Oseltamivir is a widely used influenza virus neuraminidase (NA) inhibitor that prevents the release of new virus particles from host cells. However, oseltamivir-resistant strains have emerged, but effective drugs against them have not yet been developed. Elucidating the binding mechanisms between NA and oseltamivir may provide valuable information for the design of new drugs against NA mutants resistant to oseltamivir. Here, we conducted large-scale (353.4 µs) free-binding molecular dynamics simulations, together with a Markov State Model and an importance-sampling algorithm, to reveal the binding process of oseltamivir and NA. Ten metastable states and five major binding pathways were identified that validated and complemented previously discovered binding pathways, including the hypothesis that oseltamivir can be transferred from the secondary sialic acid binding site to the catalytic site. The discovery of multiple new metastable states, especially the stable bound state containing a water-mediated hydrogen bond between Arg118 and oseltamivir, may provide new insights into the improvement of NA inhibitors. We anticipated the findings presented here will facilitate the development of drugs capable of combating NA mutations.


Subject(s)
Influenza, Human , Oseltamivir , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Resistance, Viral/genetics , Enzyme Inhibitors/chemistry , Humans , Neuraminidase/chemistry , Oseltamivir/chemistry , Oseltamivir/metabolism , Oseltamivir/pharmacology
6.
Bioorg Chem ; 104: 104257, 2020 11.
Article in English | MEDLINE | ID: mdl-32927129

ABSTRACT

BACKGROUND: Oseltamivir is a first-line antiviral drug, especially in primary hospitals. During the ongoing outbreak of coronavirus disease 2019 (COVID-19), most patients with COVID-19 who are symptomatic have used oseltamivir. Considering its popular and important role as an antiviral drug, it is necessary to evaluate oseltamivir in the treatment of COVID-19. OBJECTIVE: To evaluate the effect of oseltamivir against COVID-19. METHODS: Swiss-model was used to construct the structure of the N-terminal RNA-binding domain (NRBD) of the nucleoprotein (NC), papain-like protease (PLpro), and RNA-directed RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). TM-align program was performed to compare the structure of the viral proteins with the structure of the neuraminidase of influenza A. Molecular docking was used to analyze the theoretical possibility of effective binding of oseltamivir with the active centers of the viral proteins. In vitro study was used to evaluate the antiviral efficiency of oseltamivir against SARS-CoV-2. By clinical case analysis, we statistically evaluated whether the history of oseltamivir use influenced the progression of the disease. RESULTS: The structures of NRBD, PLpro, and RdRp were built successfully. The results from TM-align suggested that the S protein, NRBD, 3C-like protease (3CLpro), PLPrO, and RdRp were structurally similar to the influenza A neuraminidase, with TM-scores of 0.30077, 0.19254, 0.28766, 0.30666, and 0.34047, respectively. Interestingly, the active center of 3CL pro was found to be similar to the active center from the neuraminidase of influenza A. Through an analysis of molecular docking, we discovered that oseltamivir carboxylic acid was more favorable to bind to the active site of 3CLpro effectively, but its inhibitory effect was not strong compared with the positive group. Finally, we used in vitro study and retrospective case analysis to verify our speculations. We found that oseltamivir is ineffective against SARS-CoV-2 in vitro study and the clinical use of oseltamivir did not improve the patients' symptoms and signs and did not slow the disease progression. CONCLUSIONS: We consider that oseltamivir isn't suitable for the treatment of COVID-19. During the outbreak of novel coronavirus, when oseltamivir is not effective for the patients after they take it, health workers should be highly vigilant about the possibility of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Oseltamivir/therapeutic use , SARS-CoV-2/drug effects , Adult , Aged , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/metabolism , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/therapeutic use , Female , Humans , Male , Middle Aged , Molecular Docking Simulation , Oseltamivir/chemistry , Oseltamivir/metabolism , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Protein Binding , RNA-Dependent RNA Polymerase/chemistry , RNA-Dependent RNA Polymerase/metabolism , Retrospective Studies , Vero Cells
7.
Genomics ; 112(6): 4427-4434, 2020 11.
Article in English | MEDLINE | ID: mdl-32745502

ABSTRACT

It is urgent to find an effective antiviral drug against SARS-CoV-2. In this study, 96 virus-drug associations (VDAs) from 12 viruses including SARS-CoV-2 and similar viruses and 78 small molecules are selected. Complete genomic sequence similarity of viruses and chemical structure similarity of drugs are then computed. A KATZ-based VDA prediction method (VDA-KATZ) is developed to infer possible drugs associated with SARS-CoV-2. VDA-KATZ obtained the best AUCs of 0.8803 when the walking length is 2. The predicted top 3 antiviral drugs against SARS-CoV-2 are remdesivir, oseltamivir, and zanamivir. Molecular docking is conducted between the predicted top 10 drugs and the virus spike protein/human ACE2. The results showed that the above 3 chemical agents have higher molecular binding energies with ACE2. For the first time, we found that zidovudine may be effective clues of treatment of COVID-19. We hope that our predicted drugs could help to prevent the spreading of COVID.


Subject(s)
Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , Molecular Docking Simulation/methods , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Host-Pathogen Interactions/drug effects , Humans , Oseltamivir/metabolism , Oseltamivir/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Zanamivir/metabolism , Zanamivir/pharmacology
8.
PLoS One ; 15(3): e0228461, 2020.
Article in English | MEDLINE | ID: mdl-32160194

ABSTRACT

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5-10 minutes. Following a brief training phase, our studies shown that iMD-VR novices were able to generate unbinding and rebinding pathways on similar timescales as iMD-VR experts, with the majority able to recover binding poses within 2.15 Å RMSD of the crystallographic binding pose. These results indicate that iMD-VR affords sufficient control for users to carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and recover crystallographic poses, offering an interesting new approach for simulating drug docking and generating binding hypotheses.


Subject(s)
HIV Protease/metabolism , Molecular Dynamics Simulation , Neuraminidase/metabolism , Trypsin/metabolism , Virtual Reality , Benzamidines/metabolism , Binding Sites , Carbamates/metabolism , Furans , Ligands , Oseltamivir/metabolism , Protein Binding , Sulfonamides/metabolism , Zanamivir/metabolism
9.
Pharmacogenomics J ; 20(4): 613-620, 2020 08.
Article in English | MEDLINE | ID: mdl-32015454

ABSTRACT

Oseltamivir, a pro-drug, is the best option for treatment and chemoprophylaxis for influenza outbreaks. However, many patients treated with oseltamivir developed adverse reactions, including hypersensitivity, gastritis, and neurological symptoms. The aim of this study was to determine the adverse drug reactions (ADRs) in Mexican patients treated with oseltamivir and whether these ADRs are associated with SNPs of the genes involved in the metabolism, transport, and interactions of oseltamivir. This study recruited 310 Mexican patients with acute respiratory diseases and treated them with oseltamivir (75 mg/day for 5 days) because they were suspected to have influenza A/H1N1 virus infection. Clinical data were obtained from medical records and interviews. Genotyping was performed using real-time polymerase chain reaction and TaqMan probes. The association was assessed under genetic models with contingency tables and logistic regression analysis. Out of 310 patients, only 38 (12.25%) presented ADRs to oseltamivir: hypersensitivity (1.9%), gastritis (10%), and depression and anxiety (0.9%). The polymorphism ABCB1-rs1045642 was associated with adverse drug reactions under the recessive model (P = 0.017); allele C was associated with no adverse drug reactions, while allele T was associated with adverse drug reactions. The polymorphisms SLC15A1-rs2297322, ABCB1-rs2032582, and CES1-rs2307243 were not consistent with Hardy-Weinberg equilibrium, and no other associations were found for the remaining polymorphisms. In conclusion, the polymorphism rs1045642 in the transporter encoded by the ABCB1 gene is a potential predictive biomarker of ADRs in oseltamivir treatment.


Subject(s)
Antiviral Agents/metabolism , Drug-Related Side Effects and Adverse Reactions/genetics , Drug-Related Side Effects and Adverse Reactions/metabolism , Oseltamivir/metabolism , Polymorphism, Single Nucleotide/genetics , Respiration Disorders/genetics , Respiration Disorders/metabolism , Acute Disease , Adolescent , Adult , Antiviral Agents/adverse effects , Biological Transport/physiology , Child , Drug Interactions/physiology , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Genetic Association Studies/methods , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Influenza, Human/genetics , Influenza, Human/metabolism , Male , Mexico/epidemiology , Middle Aged , Oseltamivir/adverse effects , Protein Transport/physiology , Respiration Disorders/drug therapy , Respiration Disorders/epidemiology , Retrospective Studies , Young Adult
10.
Cell Biochem Biophys ; 77(4): 319-333, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31559538

ABSTRACT

Influenza virus is known for its intermittent outbreaks affecting billions of people worldwide. Several neuraminidase inhibitors have been used in practice to overcome this situation. However, advent of new resistant mutants has limited its clinical utilization. In the recent years drug repurposing technique has attained the limelight as it is cost effective and reduces the time consumed for drug discovery. Here, we present multi-dimensional repurposing strategy that integrates the results of ligand-, energy-, receptor cavity, and shape-based pharmacophore algorithm to effectively identify novel drug candidate for influenza. The pharmacophore hypotheses were generated by utilizing the PHASE module of Schrödinger. The generated hypotheses such as AADP, AADDD, and DDRRNH, respectively, for ligand-, e-pharmacophore and receptor cavity based approach alongside shape of oseltamivir were successfully utilized to screen the DrugBank database. Subsequently, these models were evaluated for their differentiating ability using Enrichment calculation. Receiver operating curve and enrichment factors from the analysis indicate that the models possess better capability to screen actives from decoy set of molecules. Eventually, the hits retrieved from different hypotheses were subjected to molecular docking using Glide module of Schrödinger Suite. The results of different algorithms were then combined to eliminate false positive hits and to demonstrate reliable prediction performance than existing approaches. Of note, Pearson's correlation coefficients were calculated to examine the extent of correlation between the glide score and IC50 values. Further, the interaction profile, pharmacokinetic, and pharmacodynamics properties were analyzed for the hit compounds. The results from our analysis showed that alprostadil (DB00770) exhibits better binding affinity toward NA protein than the existing drug molecules. The biological activity of the hit was also predicted using PASS algorithm that renders the antiviral activity of the compound. Further, the results were validated using mutation analysis and molecular dynamic simulation studies. Indeed, this integrative filtering is able to exceed accuracy of other state-of-the-art methods for the drug discovery.


Subject(s)
Drug Discovery , Drug Repositioning , Algorithms , Alprostadil/chemistry , Alprostadil/metabolism , Alprostadil/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , Humans , Influenza, Human/drug therapy , Influenza, Human/pathology , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Neuraminidase/chemistry , Neuraminidase/genetics , Neuraminidase/metabolism , Oseltamivir/chemistry , Oseltamivir/metabolism , Protein Binding
11.
J Chem Phys ; 150(22): 220901, 2019 Jun 14.
Article in English | MEDLINE | ID: mdl-31202243

ABSTRACT

As molecular scientists have made progress in their ability to engineer nanoscale molecular structure, we face new challenges in our ability to engineer molecular dynamics (MD) and flexibility. Dynamics at the molecular scale differs from the familiar mechanics of everyday objects because it involves a complicated, highly correlated, and three-dimensional many-body dynamical choreography which is often nonintuitive even for highly trained researchers. We recently described how interactive molecular dynamics in virtual reality (iMD-VR) can help to meet this challenge, enabling researchers to manipulate real-time MD simulations of flexible structures in 3D. In this article, we outline various efforts to extend immersive technologies to the molecular sciences, and we introduce "Narupa," a flexible, open-source, multiperson iMD-VR software framework which enables groups of researchers to simultaneously cohabit real-time simulation environments to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. We outline several application domains where iMD-VR is facilitating research, communication, and creative approaches within the molecular sciences, including training machines to learn potential energy functions, biomolecular conformational sampling, protein-ligand binding, reaction discovery using "on-the-fly" quantum chemistry, and transport dynamics in materials. We touch on iMD-VR's various cognitive and perceptual affordances and outline how these provide research insight for molecular systems. By synergistically combining human spatial reasoning and design insight with computational automation, technologies such as iMD-VR have the potential to improve our ability to understand, engineer, and communicate microscopic dynamical behavior, offering the potential to usher in a new paradigm for engineering molecules and nano-architectures.


Subject(s)
Molecular Dynamics Simulation , Software , Virtual Reality , Benzamidines/metabolism , Cyclophilin A/chemistry , Humans , Influenza A Virus, H7N9 Subtype/enzymology , Interpersonal Relations , Ligands , Neural Networks, Computer , Neuraminidase/metabolism , Organic Chemicals/chemistry , Oseltamivir/metabolism , Protein Binding , Protein Conformation , Quantum Theory , Trypsin/metabolism
12.
Yakugaku Zasshi ; 139(5): 767-781, 2019.
Article in Japanese | MEDLINE | ID: mdl-31061347

ABSTRACT

Although the anti-influenza virus drug oseltamivir ameliorates the fever of influenza, adverse events related to its hypothermic effect have been reported. We found that oseltamivir causes dose-dependent hypothermia in normal mice, and have been studying the pharmacological mechanisms responsible for 12 years. Oseltamivir blocks nicotinic cholinergic transmission at sympathetic ganglia and reduces sympathetic modulation of brown adipose tissue (BAT), a heat generator. Oseltamivir was found to target the ion channels of nicotinic acetylcholine receptors, as demonstrated by patch clamp experiments with cells expressing the human α3ß4 nicotinic receptor. Metabolized oseltamivir carboxylate, which inhibits the influenza virus neuraminidase, did not elicit hypothermia and ion channel suppression. Body temperature was decreased by intracerebroventricular administration of oseltamivir. Because this hypothermic effect was inhibited by dopamine D2 receptor blockade, it was suggested that oseltamivir centrally stimulates the D2 receptor. In Japan, the package inserts for oseltamivir and amantadine indicate very similar adverse neuropsychiatric reactions for the two drugs (abnormal behavior, consciousness disturbance, convulsion, delirium, delusion, hallucination). A literature search revealed that in some previous studies, oseltamivir and amantadine were shown to block the ion channel systems and activate the dopaminergic nervous system via several mechanisms. Therefore the similarity of the adverse reactions elicited by oseltamivir and amantadine was considered attributable to their similar pharmacological effects.


Subject(s)
Antipyretics , Hypothermia/chemically induced , Oseltamivir/adverse effects , Oseltamivir/pharmacology , Adipose Tissue, Brown/metabolism , Amantadine , Animals , Antiviral Agents , Body Temperature/drug effects , Dose-Response Relationship, Drug , Humans , Mice , Oseltamivir/metabolism , Rats , Receptors, Dopamine D2/metabolism , Receptors, Nicotinic/metabolism
13.
J Med Chem ; 61(22): 9976-9999, 2018 11 21.
Article in English | MEDLINE | ID: mdl-30365885

ABSTRACT

Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.


Subject(s)
Drug Design , Drug Resistance, Viral/drug effects , Influenza A virus/drug effects , Mutation , Neuraminidase/genetics , Oseltamivir/chemistry , Oseltamivir/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Catalytic Domain , Dogs , Drug Resistance, Viral/genetics , Drug Stability , Humans , Influenza A virus/enzymology , Influenza A virus/genetics , Madin Darby Canine Kidney Cells , Male , Molecular Docking Simulation , Neuraminidase/chemistry , Neuraminidase/metabolism , Nitrogen/chemistry , Oseltamivir/metabolism , Oseltamivir/pharmacokinetics , Rats , Tissue Distribution
14.
Bioorg Med Chem Lett ; 28(21): 3477-3482, 2018 11 15.
Article in English | MEDLINE | ID: mdl-30266543

ABSTRACT

In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50 = 1.30 ±â€¯0.23 µM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.


Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , Neuraminidase/antagonists & inhibitors , Oseltamivir/analogs & derivatives , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Catalytic Domain , Drug Design , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Influenza A Virus, H5N1 Subtype/drug effects , Microsomes, Liver/metabolism , Molecular Docking Simulation , Neuraminidase/chemistry , Oseltamivir/chemical synthesis , Oseltamivir/metabolism
15.
Mol Pharm ; 15(9): 3871-3880, 2018 09 04.
Article in English | MEDLINE | ID: mdl-30095924

ABSTRACT

Carboxylesterase-1 (CE-1) is a crucial enzyme responsible for metabolism/activation/inactivation of xenobiotics (therapeutic agents, prodrugs, abused drugs, and organophosphorus nerve agents etc.) and also involved in many other biological processes. In this study, we performed extensive computational modeling and simulations to understand the fundamental reaction mechanism of cocaine hydrolysis catalyzed by CE-1, revealing that CE-1-catalyzed cocaine hydrolysis follows a novel reaction pathway with only two reaction steps: a single-step acylation process and a single-step deacylation process. In the transition states of both single-step processes, the cocaine NH group joins the oxyanion hole to form an additional hydrogen bond with the negatively charged carbonyl oxygen atom of the cocaine. Thus, the transition states are stabilized by both intermolecular and intramolecular hydrogen bonds with the methyl ester of cocaine, specifically the carbonyl oxygen atom. The rate-limiting transition state is associated with the acylation process, and the activation free energy barrier was predicted to be 20.1 kcal/mol. Further, in vitro experimental kinetic analysis was performed for human CE-1-catalyzed cocaine hydrolysis. For CE-1-catalyzed cocaine hydrolysis, the computationally predicted free energy barrier (20.1 kcal/mol) is reasonably close to the experimentally derived turnover number ( kcat = 0.058 min-1), indicating the reasonability of the computational results. The obtained novel mechanistic insights are expected to benefit not only CE-1 related rational drug discovery but also future research on the catalytic mechanism of other esterases.


Subject(s)
Carboxylic Ester Hydrolases/metabolism , Cocaine/metabolism , Catalysis , Dabigatran/metabolism , Humans , Hydrolysis , Kinetics , Oseltamivir/metabolism
16.
Cell Biochem Biophys ; 76(3): 357-376, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29687225

ABSTRACT

The Influenza A virus is one of the principle causes of respiratory illness in human. The surface glycoprotein of the influenza virus, neuraminidase (NA), has a vital role in the release of new viral particle and spreads infection in the respiratory tract. It has been long recognized as a valid drug target for influenza A virus infection. Oseltamivir is used as a standard drug of choice for the treatment of influenza. However, the emergence of mutants with novel mutations has increased the resistance to potent NA inhibitor. In the present investigation, we have employed computer-assisted combinatorial techniques in the screening of 8621 molecules from Drug Bank to find potent NA inhibitors. A three-dimensional pharmacophore model was generated from the previously reported 28 carbocylic influenza NA inhibitors along with oseltamivir using PHASE module of Schrödinger Suite. The model generated consists of one hydrogen bond acceptor (A), one hydrogen bond donors (D), one hydrophobic group (H), and one positively charged group (P), ADHP. The hypothesis was further validated for its integrity and significance using enrichment analysis. Subsequently, an atom-based 3D-QSAR model was built using the common pharmacophore hypothesis (CPH). The developed 3D-QSAR model was found to be statistically significant with R2 value of 0.9866 and Q2 value of 0.7629. Further screening was accomplished using three-stage docking process using the Glide algorithm. The resultant lead molecules were examined for its drug-like properties using the Qikprop algorithm. Finally, the calculated pIC50 values of the lead compounds were validated by the AutoQSAR algorithm. Overall, the results from our analysis highlights that lisinopril (DB00722) is predicted to bind better with NA than currently approved drug. In addition, it has the best match in binding geometry conformations with the existing NA inhibitor. Note that the antiviral activity of lisinopril is reported in the literature. However, our paper is the first report on lisinopril activity against influenza A virus infection. These results are envisioned to help design the novel NA inhibitors with an increased antiviral efficacy.


Subject(s)
Drug Repositioning/methods , Enzyme Inhibitors/metabolism , Neuraminidase/antagonists & inhibitors , Quantitative Structure-Activity Relationship , Antiviral Agents/therapeutic use , Binding Sites , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Hydrogen Bonding , Influenza, Human/drug therapy , Ligands , Lisinopril/chemistry , Lisinopril/metabolism , Lisinopril/therapeutic use , Molecular Conformation , Neuraminidase/metabolism , Oseltamivir/chemistry , Oseltamivir/metabolism , Oseltamivir/therapeutic use
17.
J Biomol Struct Dyn ; 36(16): 4255-4269, 2018 Dec.
Article in English | MEDLINE | ID: mdl-29199545

ABSTRACT

Oseltamivir (Tamiflu) is the most accepted antiviral drug that targets the neuraminidase (NA) protein to inhibit the viral release from the host cell. Few H1N1 influenza strains with the H274Y mutation creates drug resistance to oseltamivir. In this study, we report that flavonoid cyanidin-3-sambubiocide (C3S) compound acts as a potential inhibitor against H274Y mutation. The drug resistance mechanism and inhibitory activity of C3S and oseltamivir against wild-type (WT) and H274Y mutant-type (MT) have been studied and compared based on the results of molecular docking, molecular dynamics, and quantum chemical methods. Oseltamivir has been found less binding affinity with MT. C3S has more binding affinity with WT and MT proteins. From the dynamical study, the 150th loop of the MT protein has found more deformation than WT. A single H274Y mutation induces the conformational changes in the 150th loop which leads to produce more resistance to oseltamivir. The 150th cavity is more attractive target for C3S to stop the conformational changes in the MT, than 430th cavity of NA protein. The C3S is stabilized with MT by more number of hydrogen bonds than oseltamivir. The electrostatic interaction energy shows a stronger C3S binding with MT and this compound may be more effective against oseltamivir-resistant virus strains.


Subject(s)
Anthocyanins/pharmacology , Disaccharides/pharmacology , Drug Resistance, Viral/drug effects , Influenza A Virus, H1N1 Subtype/drug effects , Mutant Proteins/antagonists & inhibitors , Mutation, Missense , Neuraminidase/antagonists & inhibitors , Anthocyanins/chemistry , Anthocyanins/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Disaccharides/chemistry , Disaccharides/metabolism , Drug Resistance, Viral/genetics , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/prevention & control , Influenza, Human/virology , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Mutant Proteins/chemistry , Mutant Proteins/metabolism , Neuraminidase/chemistry , Neuraminidase/metabolism , Oseltamivir/chemistry , Oseltamivir/metabolism , Oseltamivir/pharmacology , Protein Binding , Protein Domains
18.
Chem Biol Drug Des ; 91(1): 105-115, 2018 01.
Article in English | MEDLINE | ID: mdl-28646621

ABSTRACT

Neuraminidase, which plays a critical role in the influenza virus life cycle, is a target for new therapeutic agents. The study of structure-activity relationships revealed that the C-5 position amino group of oseltamivir was pointed to 150-cavity of the neuraminidase in group 1. This cavity is important for selectivity of inhibitors against N1 versus N2 NA. A serial of influenza neuraminidase inhibitors with the oseltamivir scaffold containing lipophilic side chains at the C-5 position have been synthesized and evaluated for their influenza neuraminidase inhibitory activity and selectivity. The results indicated that compound 13o (H5N1 IC50  = 0.1 ± 0.04 µm, H3N2 IC50  = 0.26 ± 0.18 µm) showed better inhibitory activity and selectivity against the group 1 neuraminidase. This study may provide a clue to design of better group 1 neuraminidase inhibitors.


Subject(s)
Enzyme Inhibitors/metabolism , Neuraminidase/antagonists & inhibitors , Oseltamivir/metabolism , Binding Sites , Catalytic Domain , Enzyme Inhibitors/chemistry , Humans , Hydrophobic and Hydrophilic Interactions , Influenza A Virus, H3N2 Subtype/enzymology , Influenza A Virus, H5N1 Subtype/enzymology , Inhibitory Concentration 50 , Molecular Docking Simulation , Neuraminidase/metabolism , Oseltamivir/chemistry , Structure-Activity Relationship
19.
Int J Clin Pharmacol Ther ; 55(9): 761-768, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28737128

ABSTRACT

BACKGROUND: The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu® (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. METHODS: This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70 - 143% for Cmax, 80 - 125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. RESULTS: Characteristics of the 20 male volunteers included were as follows: mean age 23 (± 0.7, SD) years (range 21 - 24 years); weight 69 (± 7.1) kg (range 60 - 88 kg); height 177 (± 5.9) cm (range 168 - 192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3 - 114.8%) for Cmax, 104.4% (95.7 - 113.9%) for AUC0-t, and 104.4% (95.6 - 113.9%) for AUC0-∞. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3 - 112.8%) for Cmax, 101.7% (96.6 - 107.1%) for AUC0-t, and 101.4% (96.5 - 106.5%) for AUC0-∞. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. CONCLUSIONS: The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers.
.


Subject(s)
Oseltamivir/metabolism , Oseltamivir/pharmacokinetics , Adult , Area Under Curve , Asian People , Biological Availability , Capsules/metabolism , Capsules/pharmacokinetics , Chemistry, Pharmaceutical/methods , Cross-Over Studies , Drugs, Generic/metabolism , Drugs, Generic/pharmacokinetics , Healthy Volunteers , Humans , Male , Oseltamivir/analogs & derivatives , Therapeutic Equivalency , Young Adult
20.
Nucleosides Nucleotides Nucleic Acids ; 36(7): 435-451, 2017 Jul 03.
Article in English | MEDLINE | ID: mdl-28548600

ABSTRACT

The possible interaction between the antiviral drug oseltamivir and calf thymus DNA at physiological pH was studied by spectrophotometry, competitive spectrofluorimetry, differential pulse voltammogram (DPV), circular dichroism spectroscopy (CD), viscosity measurements, salt effect, and computational studies. Intercalation of oseltamivir between the base pairs of DNA was shown by a sharp increase in specific viscosity of DNA and a decrease of the peak current and a positive shift in differential pulse voltammogram. Competitive fluorescence experiments were performed using neutral red (NR) as a probe for the intercalation binding mode. The studies showed that oseltamivir is able to release the NR.


Subject(s)
Antiviral Agents/metabolism , DNA/metabolism , Molecular Docking Simulation , Oseltamivir/metabolism , Animals , Antiviral Agents/chemistry , Cattle , DNA/chemistry , Nucleic Acid Conformation , Oseltamivir/chemistry , Spectrum Analysis , Viscosity
SELECTION OF CITATIONS
SEARCH DETAIL
...