We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CL
of the severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2) causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CL
inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CL
enzyme of the closely related SARS-CoV virus. The top-ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CL
substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CL
. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CL
inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.
The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that ...subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility.
The aggregation of amyloid-β protein (1-42) is studied at experimental concentrations using all-atom molecular dynamics simulations. We observe a fast aggregation into oligomers without significant ...changes in the internal structure of individual proteins. The aggregation process is characterized in terms of transition networks.
Sickle cell disease is a hemoglobinopathy resulting from a point mutation from glutamate to valine at position six of the β‐globin chains of hemoglobin. This mutation gives rise to pathological ...aggregation of the sickle hemoglobin and, as a result, impaired oxygen binding, misshapen and short‐lived erythrocytes, and anemia. We aim to understand the structural effects caused by the single Glu6Val mutation leading to protein aggregation. To this end, we perform multiscale molecular dynamics simulations employing atomistic and coarse‐grained models of both wild‐type and sickle hemoglobin. We analyze the dynamics of hemoglobin monomers and dimers, study the aggregation of wild‐type and sickle hemoglobin into decamers, and analyze the protein–protein interactions in the resulting aggregates. We find that the aggregation of sickle hemoglobin is driven by both hydrophobic and electrostatic protein–protein interactions involving the mutation site and surrounding residues, leading to an extended interaction area and thus stable aggregates. The wild‐type protein can also self‐assemble, which, however, results from isolated interprotein salt bridges that do not yield stable aggregates. This knowledge can be exploited for the development of sickle hemoglobin‐aggregation inhibitors.
In this simulation study, we present a comparison of the secondary structure of the two major alloforms of the Alzheimer’s peptide (Aβ1–40 and Aβ1–42) on the basis of molecular dynamics (MD) ...simulations on thea microsecond time scale using the two GROMOS96 force fields ffG43a2 and ffG53a6. We observe peptide and force-field related differences in the sampled conformations of Aβ1–40 and Aβ1–42, which we characterize in terms of NMR chemical shifts calculated from the MD trajectories and validate against the corresponding experimental NMR results. From this analysis, we can conclude that ffG53a6 is better able to model the structural propensities of Aβ1–40 and Aβ1–42 than ffG43a2. Furthermore, we provide a description of the influences of pH and binding of D3, a 12-residue d-enantiomeric peptide with demonstrated antiamyloid effects, on the structure of Aβ1–42. We demonstrate that, under slightly acidic conditions, protonation of the three histidine residues in Aβ1–42 promotes the formation of β-sheets via a reduction in electrostatic repulsion between the two terminal regions. Our studies further reveal that the binding between D3 and Aβ1–42 is driven by electrostatic interactions between negatively charged Aβ1–42 residues and the five positively charged arginine residues of D3. The binding of D3 was found to induce large conformational changes in the amyloid peptide, with a reduction in β-sheet units being the most significant effect recorded, possibly explaining the observed amyloid-inhibiting properties of the d-peptide.
A brief history of amyloid aggregation simulations Fatafta, Hebah; Khaled, Mohammed; Kav, Batuhan ...
Wiley interdisciplinary reviews. Computational molecular science,
January/February 2024, 2024-01-00, 20240101, Letnik:
14, Številka:
1
Journal Article
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Amyloid proteins are characterized by their tendency to aggregate into amyloid fibrils, which are often associated with devastating diseases. Aggregation pathways typically involve unfolding or ...misfolding of monomeric proteins and formation of transient oligomers and protofibrils before the final aggregation product is formed. The conformational dynamics and polymorphic and volatile nature of these aggregation intermediates make their characterization by experimental techniques alone insufficient and also require computational approaches. Over the past 25 years, the size of simulated amyloid aggregation systems and the length of these simulations have increased significantly. These advances are discussed here. The review includes simulation approaches that model the aggregating peptides or proteins at both the all‐atom and coarse‐grained levels, use molecular dynamics simulations or Monte Carlo sampling to simulate the conformational changes, and present results for various amyloid peptides and proteins ranging from Lys‐Phe‐Phe‐Glu (KFFE) as the smallest system to Aβ$$ \mathrm{A}\upbeta $$ as an intermediate‐sized peptide to α‐synuclein. The presentation of the history of amyloid aggregation simulations concludes with a discussion of where the future of these simulations may lie.
This article is categorized under:
Structure and Mechanism > Computational Biochemistry and Biophysics
Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods
Amyloid proteins tend to aggregate into oligomers, protofibrils and fibrils, which is associated with severe diseases. The study of their aggregation pathways involves computational approaches using both all‐atom and coarse‐grained models through molecular dynamics simulations or Monte Carlo sampling. The review summarizes these simulations from their beginnings to the present day.
Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in ...the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12- and 15-mers under consideration in recent years.
Computer simulations of protein-membrane systems Loschwitz, Jennifer; Olubiyi, Olujide O; Hub, Jochen S ...
Progress in molecular biology and translational science,
2020, Letnik:
170
Journal Article
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The interactions between proteins and membranes play critical roles in signal transduction, cell motility, and transport, and they are involved in many types of diseases. Molecular dynamics (MD) ...simulations have greatly contributed to our understanding of protein-membrane interactions, promoted by a dramatic development of MD-related software, increasingly accurate force fields, and available computer power. In this chapter, we present available methods for studying protein-membrane systems with MD simulations, including an overview about the various all-atom and coarse-grained force fields for lipids, and useful software for membrane simulation setup and analysis. A large set of case studies is discussed.
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•Molecular dynamics simulations of ≈150 3CLpro-compound complexes identified 34 strong ligands.•About two third of the 15 compounds screened in a fluorescence 3CLpro activity assay ...are hits.•Inhibition of 3CLpro by more than 80% at 20 μM of the best hits.•Several drugs and natural products among the inhibitors that may be used for drug repurposing.•Testosterone was revealed as endogenous 3CLpro inhibitor.
For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CLpro, which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CLpro’s binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CLpro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CLpro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CLpro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.
Enteroaggregative Escherichia coli (EAEC) is a predominant but neglected enteric pathogen implicated in infantile diarrhoea and nutrient malabsorption. There are no non-antibiotic approaches to ...dealing with persistent infection by these exceptional colonizers, which form copious biofilms. We screened the Medicines for Malaria Venture Pathogen Box for chemical entities that inhibit EAEC biofilm formation.
We used EAEC strains, 042 and MND005E in a medium-throughput crystal violet-based antibiofilm screen. Hits were confirmed in concentration-dependence, growth kinetic and time course assays and activity spectra were determined against a panel of 25 other EAEC strains. Antibiofilm activity against isogenic EAEC mutants, molecular docking simulations and comparative genomic analysis were used to identify the mechanism of action of one hit.
In all, five compounds (1.25%) reproducibly inhibited biofilm accumulation by at least one strain by 30-85% while inhibiting growth by under 10%. Hits exhibited potent antibiofilm activity at concentrations at least 10-fold lower than those reported for nitazoxanide, the only known EAEC biofilm inhibitor. Reflective of known EAEC heterogeneity, only one hit was active against both screen isolates, but three hits showed broad antibiofilm activity against a larger panel of strains. Mechanism of action studies point to the EAEC anti-aggregation protein (Aap), dispersin, as the target of compound MMV687800.
This study identified five compounds, not previously described as anti-adhesins or Gram-negative antibacterials, with significant EAEC antibiofilm activity. Molecule, MMV687800 targets the EAEC Aap. In vitro small-molecule inhibition of EAEC colonization opens a way to new therapeutic approaches against EAEC infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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