The COVID-19 pandemic caused by SARS-CoV-2 virus has created a global damage and has exposed the vulnerable side of scientific research towards novel diseases. The intensity of the pandemic is huge, with mortality rates of more than 6 million people worldwide in a span of 2 years. Considering the gravity of the situation, scientists all across the world are continuously attempting to create successful therapeutic solutions to combat the virus. Various vaccination strategies are being devised to ensure effective immunization against SARS-CoV-2 infection. SARS-CoV-2 spreads very rapidly, and the infection rate is remarkably high than other respiratory tract viruses. The viral entry and recognition of the host cell is facilitated by S protein of the virus. N protein along with NSP3 is majorly responsible for viral genome assembly and NSP12 performs polymerase activity for RNA synthesis. In this study, we have designed a multi-epitope, chimeric vaccine considering the two structural (S and N protein) and two non-structural proteins (NSP3 and NSP12) of SARS-CoV-2 virus. The aim is to induce immune response by generating antibodies against these proteins to target the viral entry and viral replication in the host cell. In this study, computational tools were used, and the reliability of the vaccine was verified using molecular docking, molecular dynamics simulation and immune simulation studies in silico. These studies demonstrate that the vaccine designed shows steady interaction with Toll like receptors with good stability and will be effective in inducing a strong and specific immune response in the body.Communicated by Ramaswamy H. Sarma.
- MeSH
- COVID-19 * prevence a kontrola MeSH
- epitopy B-lymfocytární MeSH
- lidé MeSH
- pandemie prevence a kontrola MeSH
- reprodukovatelnost výsledků MeSH
- SARS-CoV-2 metabolismus MeSH
- simulace molekulového dockingu MeSH
- vakcíny proti COVID-19 MeSH
- virové vakcíny * chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The misuse of novichok agents in assassination attempts has been reported in the international media since 2018. These relatively new class of neurotoxic agents is claimed to be more toxic than the agents of the G and V series and so far, there is no report yet in literature about potential antidotes against them. To shed some light into this issue, we report here the design and synthesis of NTMGMP, a surrogate of A-242 and also the first surrogate of a novichok agent useful for experimental evaluation of antidotes. Furthermore, the efficiency of the current commercial oximes to reactivate NTMGMP-inhibited acetylcholinesterase (AChE) was evaluated. The Ellman test was used to confirm the complete inhibition of AChE, and to compare the subsequent rates of reactivation in vitro as well as to evaluate aging. In parallel, molecular docking, molecular dynamics and MM-PBSA studies were performed on a computational model of the human AChE (HssAChE)/NTMGMP complex to assess the reactivation performances of the commercial oximes in silico. Experimental and theoretical studies matched the exact hierarchy of efficiency and pointed to trimedoxime as the most promising commercial oxime for reactivation of AChE inhibited by A-242.
- MeSH
- acetylcholinesterasa MeSH
- antidota farmakologie MeSH
- cholinesterasové inhibitory toxicita MeSH
- lidé MeSH
- nervová bojová látka * toxicita MeSH
- oximy farmakologie MeSH
- reaktivátory cholinesterázy * farmakologie MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In this work the DBL3x domain of the erythrocyte membrane protein from Plasmodium Falciparum (PfEMP1), was revisited as a potential molecular target for the development of new drugs against malaria. This protein interacts with chondroitin sulfate A (CSA), a glycosaminoglycan present in the substance fundamental for connective tissues of vertebrates and is implicated in malaria complications in pregnant women. We performed molecular docking and molecular dynamic studies of DBL3x complexed with CSA and five analogues, where the sulfate group was replaced by phosphate, in order to evaluate if the better electrostatic interactions provided by phosphate groups could afford better binders capable of preventing the binding of CSA to DBL3x. Results suggest that all proposed compounds have high affinity towards DBL3x and could bind better to the DBL3x domain of PfEMP1 than CSA, qualifying as potential inhibitors of this protein and, therefore, new potential leads for the drug design against malaria.Communicated by Ramaswamy H. Sarma.
- MeSH
- antigeny protozoální chemie MeSH
- chondroitin sulfáty chemie metabolismus farmakologie MeSH
- erytrocyty metabolismus MeSH
- fosfáty MeSH
- glykosaminoglykany metabolismus MeSH
- lidé MeSH
- malárie * komplikace metabolismus MeSH
- membránové proteiny metabolismus MeSH
- parazitární komplikace těhotenství * metabolismus MeSH
- placenta metabolismus MeSH
- Plasmodium falciparum chemie MeSH
- protozoální proteiny chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- sírany metabolismus MeSH
- těhotenství MeSH
- tropická malárie * farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
- MeSH
- COVID-19 * MeSH
- cysteinové endopeptidasy MeSH
- farmakoterapie COVID-19 MeSH
- inhibitory proteas MeSH
- koronavirové proteasy 3C MeSH
- léčivé přípravky MeSH
- lidé MeSH
- SARS-CoV-2 * MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
- MeSH
- algoritmy MeSH
- chemické bojové látky chemie MeSH
- ligandy MeSH
- molekulární konformace MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- ricin antagonisté a inhibitory chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.
- MeSH
- acetylcholinesterasa chemie účinky léků MeSH
- katalytická doména MeSH
- kvantová teorie MeSH
- lidé MeSH
- molekulární konformace MeSH
- organothiofosforové sloučeniny farmakologie MeSH
- pralidoximové sloučeniny chemie farmakologie MeSH
- protony MeSH
- serin chemie MeSH
- simulace molekulární dynamiky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hydrazones and their derivatives are very important compounds in medicinal chemistry due to their reported biological activity for the treatment of several diseases, like Alzheimer's, cancer, inflammation, and leishmaniasis. However, most of the investigations on hydrazones available in literature today are directed to the synthesis of these molecules with little discussion available on their biological activities. With the purpose of bringing lights into this issue, we performed a revision of the literature and wrote this review based on some of the most current research reports of hydrazones and derivatives, making it clear that the synthesis of these molecules can lead to new drug prototypes. Our goal is to encourage more studies focused on the synthesis and evaluation of new hydrazones, as a contribution to the development of potential new drugs for the treatment of various diseases.
- MeSH
- hydrazony chemická syntéza farmakologie MeSH
- lidé MeSH
- molekulární struktura MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
