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Computers in Biology and Medicine Aug 2021Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The virus that causes the disease, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2),...
Coronavirus disease 2019 (COVID-19) is an ongoing pandemic. The virus that causes the disease, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), predominantly infects the respiratory tract, which may lead to pneumonia and death in severe cases. Many marine compounds have been found to have immense medicinal value and have gained approval from the Food and Drug Administration (FDA), and some are being tested in clinical trials. In the current investigation, we redirected a number of marine compounds toward SARS-CoV-2 by targeting the main protease (M, PDB ID: 6Y2F), subjecting them to several advanced computational techniques using co-crystallised ligand as the reference compound. The results of the binding affinity studies showed that two compounds, eribulin mesylate (eri) and soblidotin (sob), displayed higher docking scores than did the reference compound. When these compounds were assessed using molecular dynamics simulation, it was evident that they demonstrated stable binding at the binding pocket of the target protein. The systems demonstrated stable root mean square deviation and radius of gyration values, while occupying the binding pocket during the simulation run. Furthermore, the essential dynamics and free energy landscape exploration revealed that the protein had navigated through a minimal energy basin and demonstrated favourable conformation while binding to the proposed inhibitors. Collectively, our findings suggest that two marine compounds, namely eri and sob, show potential as SARS-CoV-2 main protease inhibitors.
Topics: Antiviral Agents; Aquatic Organisms; Biological Products; Coronavirus 3C Proteases; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Protease Inhibitors; SARS-CoV-2
PubMed: 34252682
DOI: 10.1016/j.compbiomed.2021.104525 -
Frontiers in Molecular Biosciences 2020Although it is known crocin, a hydrophilic compound from the herbal plant L., has promising antitumor activity, the detailed mechanism of its antitumor activity was not...
Although it is known crocin, a hydrophilic compound from the herbal plant L., has promising antitumor activity, the detailed mechanism of its antitumor activity was not well understood. Recent experiments suggested tubulin as the primary target for the antitumor activity of crocin. However, due to a lack of crystal structure of tubulin bound with crocin, the exact binding mode and interaction between crocin and tubulin remains exclusive. In the present work, a computational study by integrating multiple conformation docking, molecular dynamics simulation as well as residue interaction network analysis was performed to investigate the molecular mechanism of crocin-tubulin interaction. By comparing the docking score, the most likely binding mode CRO_E1 were identified from 20 different binding modes of crocin in the vinca binding pockets. Further molecular dynamics simulation of CRO_E1 complex showed the binding of crocin is more stable than the inhibitor soblidotin and vinblastine. During the simulation course, an excessive number of hydrogen bonds were observed for the ligand crocin. The binding free energy of crocin-tubulin complex was calculated as -79.25 ± 7.24 kcal/mol, which is almost twice of the ligand soblidotin and vinblastine. By using energy decomposition, hot residues for CRO_E1 were identified as Gln, Gln, Thr, Ser, Pro-Lys-Val-Ser-Asp, Tyr, and Asn in the β-chain, and Asp, Ala-Leu, Val, Asn, and Ile in the α-chain. Residue interaction network analysis also showed the importance of these hot residues in the interaction network of crocin-tubulin complex. In addition, a common residue motif Val-Xxx-Asp was discovered for all three bindings, suggesting its importance in future drug design. The study could provide valuable insights into the interaction between crocin and tubulin, and give suggestive clues for further experimental studies.
PubMed: 33251248
DOI: 10.3389/fmolb.2020.586970 -
Molecules (Basel, Switzerland) Mar 2019This work presents an account of the reactivity behavior of the anticancer marine drugs, Soblidotin and Tasidotin, based on the calculation of the global and local...
This work presents an account of the reactivity behavior of the anticancer marine drugs, Soblidotin and Tasidotin, based on the calculation of the global and local descriptors resulting from Chemical Reactivity Theory (CRT), also known as Conceptual DFT, for their consideration as a useful complement to approximations based on Molecular Docking. The information on the global and local reactivity descriptors of the Soblidotin and Tasidotin molecules, obtained through our proposed methodology, may be used for the design of new pharmaceutical analogs by relying on the chemical interactions between these peptides and their protein-type biological receptors. It can be concluded that the CRT approximation to the global and local chemical reactivity, based on the descriptors, can provide interesting information for the consideration of both molecules as potential therapeutic drugs. This is complemented by a study on Advanced Glycation Endproduct (AGE) inhibition, by comparison with the usual molecular systems considered for the task, as a re-purposing study. Finally, the bioactivity scores for Soblidotin and Tasidotin are predicted through an empirical procedure, based on comparison with molecular structures with well-known pharmacological properties.
Topics: Antimicrobial Cationic Peptides; Antineoplastic Agents; Aquatic Organisms; Glycation End Products, Advanced; Models, Molecular; Molecular Conformation; Peptides; Structure-Activity Relationship
PubMed: 30901820
DOI: 10.3390/molecules24061115 -
MAbs 2017Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer...
Targeted therapeutics that can differentiate between normal and malignant tumor cells represent the ideal standard for the development of a successful anti-cancer strategy. The Sialyl-Thomsen-nouveau antigen (STn or Sialyl-Tn, also known as CD175s) is rarely seen in normal adult tissues, but it is abundantly expressed in many types of human epithelial cancers. We have identified novel antibodies that specifically target with high affinity the STn glycan independent of its carrier protein, affording the potential to recognize a wider array of cancer-specific sialylated proteins. A panel of murine monoclonal anti-STn therapeutic antibodies were generated and their binding specificity and efficacy were characterized in vitro and in in vivo murine cancer models. A subset of these antibodies were conjugated to monomethyl auristatin E (MMAE) to generate antibody-drug conjugates (ADCs). These ADCs demonstrated in vitro efficacy in STn-expressing cell lines and significant tumor growth inhibition in STn-expressing tumor xenograft cancer models with no evidence of overt toxicity.
Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Agents, Immunological; Breast Neoplasms; Cell Line, Tumor; Drug Delivery Systems; Female; Humans; Mice; Mice, Inbred BALB C; Oligopeptides
PubMed: 28281872
DOI: 10.1080/19420862.2017.1290752 -
Marine Drugs Apr 2016A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of...
A conformational restriction strategy was used to design and synthesize nine TZT-1027 analogues. 3-Aryl-azetidine moiety was used to replace phenylethyl group of TZT-1027 at the C-terminus. These analogues exhibited moderate to excellent antiproliferative activities, and the most potent compound 1a showed IC50 values of 2.2 nM against A549 and 2.1 nM against HCT116 cell lines, respectively. However, 1a could not achieve effective inhibition at all the dose levels in the A549 xenograft model (up to 5 mg/kg, injection, once a day), which is only 16%-35% inhibition at the end of the experiment.
Topics: A549 Cells; Animals; Antineoplastic Agents; Azetidines; Cell Line, Tumor; Cell Proliferation; Female; HCT116 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Oligopeptides
PubMed: 27136567
DOI: 10.3390/md14050085 -
Analytical Cellular Pathology... 2015Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In... (Review)
Review
Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.
Topics: Antineoplastic Agents; Humans; Microtubules; Neoplasms
PubMed: 26484003
DOI: 10.1155/2015/690916 -
Cancer Science Feb 2009TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD)...
TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ≤2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks.
Topics: Adult; Aged; Antineoplastic Agents; Depsipeptides; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Oligopeptides; Polymerization; Survival Rate; Treatment Outcome; Tubulin; Tubulin Modulators
PubMed: 19068085
DOI: 10.1111/j.1349-7006.2008.01023.x -
EMBO Reports Nov 2008The tubulin vinca domain is the target of widely different microtubule inhibitors that interfere with the binding of vinblastine. Although all these ligands inhibit the...
The tubulin vinca domain is the target of widely different microtubule inhibitors that interfere with the binding of vinblastine. Although all these ligands inhibit the hydrolysis of GTP, they affect nucleotide exchange to variable extents. The structures of two vinca domain antimitotic peptides--phomopsin A and soblidotin (a dolastatin 10 analogue)--bound to tubulin in a complex with a stathmin-like domain show that their sites partly overlap with that of vinblastine and extend the definition of the vinca domain. The structural data, together with the biochemical results from the ligands we studied, highlight two main contributors in nucleotide exchange: the flexibility of the tubulin subunits' arrangement at their interfaces and the residues in the carboxy-terminal part of the beta-tubulin H6-H7 loop. The structures also highlight common features of the mechanisms by which vinca domain ligands favour curved tubulin assemblies and destabilize microtubules.
Topics: Ligands; Microtubules; Models, Molecular; Mycotoxins; Oligopeptides; Protein Structure, Tertiary; Tubulin; Vinblastine
PubMed: 18787557
DOI: 10.1038/embor.2008.171 -
Anticancer Research 2007TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim...
BACKGROUND
TZT-1027 (Soblidotin), a microtubule (MT)-depolymerizing agent, has antivascular activity through the disruption of microtubules in vascular endothelial cells. Our aim was to elucidate the mechanism of TZT-1027-induced antivascular activity by investigating the impact of various inhibitors.
MATERIALS AND METHODS
The inhibitory effects on TZT-1027-induced antivascular activity were evaluated by a tumor perfusion study in mice bearing Colon26 tumors and a vascular permeability study on human umbilical vein endothelial cells monolayer. Western blotting analyses were performed to verify the mechanism of antivascular activity.
RESULTS
Pretreatment with docetaxel and SB220025, a p38 mitogen-activated protein kinase (MAPK) inhibitor, significantly suppressed the TZT-1027-induced reduction of tumor perfusion and increase in vascular permeability. Gross findings showed that SB220025 visibly attenuated the TZT-1027-induced widespread hemorrhage in tumors. Western blotting analyses revealed that TZT-1027 induced the phosphorylation of p38 MAPK only slightly compared to hydrogen peroxide, and that docetaxel and SB220025 increased the acetylation of alpha-tubulin an effect opposite to that of TZT-1027.
CONCLUSION
TZT-1027-induced antivascular activity was abolished by docetaxel through the stabilization of microtubules, and by p38 MAPK inhibitor not only through the regulation of the p38 MAPK pathway, but also through the direct stabilization of microtubules, similar to docetaxel.
Topics: Adenocarcinoma; Animals; Blotting, Western; Capillary Permeability; Colonic Neoplasms; Docetaxel; Drug Interactions; Endothelial Cells; Female; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Oligopeptides; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Taxoids; p38 Mitogen-Activated Protein Kinases
PubMed: 18225550
DOI: No ID Found -
British Journal of Cancer May 2007TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect...
TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to gamma-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.
Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Cycle; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Mammary Neoplasms, Animal; Mice; Mice, Nude; Microtubules; Models, Biological; Oligopeptides; Radiation-Sensitizing Agents; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 17473826
DOI: 10.1038/sj.bjc.6603769