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The number of cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) has reached over 114,000. SARS-CoV-2 caused a pandemic in Wuhan, China, in December 2019 and is rapidly spreading globally. It has been reported that peptide-like anti-HIV-1 drugs are effective against SARS-CoV Main protease (M pro ). Due to the close phylogenetic relationship between SARS-CoV and SARS-CoV-2, their main proteases share many structural and functional features. Thus, these drugs are also regarded as potential drug candidates targeting SARS-CoV-2 M pro . However, the mechanism of action of SARS-CoV-2 M pro at the atomic-level is unknown. In the present study, we revealed key interactions between SARS-CoV-2 M pro and three drug candidates by performing pharmacophore modeling and 1 μs molecular dynamics (MD) simulations. His41, Gly143, and Glu166 formed interactions with the functional groups that were common among peptide-like inhibitors in all MD simulations. These interactions are important targets for potential drugs against SARS-CoV-2 M pro .

Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches. Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.

DNA methylation is an epigenetic mechanism that introduces a methyl group at the C5 position of cytosine. This reaction is catalyzed by DNA methyltransferases (DNMTs) and is essential for the regulation of gene transcription. The DNMT1 and DNMT3A or -3B family proteins are known targets for the inhibition of DNA hypermethylation in cancer cells. A selective non-nucleoside DNMT3A inhibitor was developed that mimics S-adenosyl-l-methionine and deoxycytidine; however, the mechanism of selectivity is unclear because the inhibitor–protein complex structure determination is absent. Therefore, we performed docking and molecular dynamics simulations to predict the structure of the complex formed by the association between DNMT3A and the selective inhibitor. Our simulations, binding free energy decomposition analysis, structural isoform comparison, and residue scanning showed that Arg688 of DNMT3A is involved in the interaction with this inhibitor, as evidenced by its significant contribution to the binding free energy. The presence of Asn1192 at the corresponding residues in DNMT1 results in a loss of affinity for the inhibitor, suggesting that the interactions mediated by Arg688 in DNMT3A are essential for selectivity. Our findings can be applied in the design of DNMT-selective inhibitors and methylation-specific drug optimization procedures.

Baloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October 2018, drug resistant viruses have already been detected from clinical trials owing to an I38 mutation of CEN. To investigate the reduction of drug sensitivity by the I38 mutant variants, we performed a molecular dynamics (MD) simulation on the CEN-BXM complex structure to analyze variations in the mode of interaction. Our simulation results suggest that the side chain methyl group of I38 in CEN engages in a CH-pi interaction with the aromatic ring of BXM. This interaction is abolished in various I38 mutant variants. Moreover, MD simulation on various mutation models and binding free energy prediction by MM/GBSA method suggest that the I38 mutation precludes any interaction with the aromatic ring of BXA and thereby reduces BXA sensitivity.

Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S -transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti . The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels.

Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can cause fatal systemic complications. Recently, we identified a potent inhibitory peptide that binds to the catalytic A-subunit of Stx. Here, using biochemical structural analysis and X-ray crystallography, we determined a minimal essential peptide motif that occupies the catalytic cavity and is required for binding to the A-subunit of Stx2a, a highly virulent Stx subtype. Molecular dynamics simulations also identified the same motif and allowed determination of a unique pharmacophore for A-subunit binding. Notably, a series of synthetic peptides containing the motif efficiently inhibit Stx2a. In addition, pharmacophore screening and subsequent docking simulations ultimately identified nine Stx2a-interacting molecules out of a chemical compound database consisting of over 7,400,000 molecules. Critically, one of these molecules markedly inhibits Stx2a both in vitro and in vivo, clearly demonstrating the significance of the pharmacophore for identifying therapeutic agents against EHEC infection.

Chagas disease results from infection by Trypanosoma cruzi and is a neglected tropical disease (NTD). Although some treatment drugs are available, their use is associated with severe problems, including adverse effects and limited effectiveness during the chronic disease phase. To develop a novel anti-Chagas drug, we virtually screened 4.8 million small molecules against spermidine synthase (SpdSyn) as the target protein using our super computer “TSUBAME2.5” and conducted in vitro enzyme assays to determine the half-maximal inhibitory concentration values. We identified four hit compounds that inhibit T . cruzi SpdSyn (TcSpdSyn) by in silico and in vitro screening. We also determined the TcSpdSyn–hit compound complex structure using X-ray crystallography, which shows that the hit compound binds to the putrescine-binding site and interacts with Asp171 through a salt bridge.

Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that causes severe human health problems. To develop a new chemotherapeutic agent for the treatment of Chagas disease, we predicted a pharmacophore model for T. cruzi dihydroorotate dehydrogenase (TcDHODH) by fragment molecular orbital (FMO) calculation for orotate, oxonate, and 43 orotate derivatives. Intermolecular interactions in the complexes of TcDHODH with orotate, oxonate, and 43 orotate derivatives were analyzed by FMO calculation at the MP2/6-31G level. The results indicated that the orotate moiety, which is the base fragment of these compounds, interacts with the Lys43, Asn67, and Asn194 residues of TcDHODH and the cofactor flavin mononucleotide (FMN), whereas functional groups introduced at the orotate 5-position strongly interact with the Lys214 residue. FMO-based interaction energy analyses revealed a pharmacophore model for TcDHODH inhibitor. Hydrogen bond acceptor pharmacophores correspond to Lys43 and Lys214, hydrogen bond donor and acceptor pharmacophores correspond to Asn67 and Asn194, and the aromatic ring pharmacophore corresponds to FMN, which shows important characteristics of compounds that inhibit TcDHODH. In addition, the Lys214 residue is not conserved between TcDHODH and human DHODH. Our analysis suggests that these orotate derivatives should preferentially bind to TcDHODH, increasing their selectivity. Our results obtained by pharmacophore modeling provides insight into the structural requirements for the design of TcDHODH inhibitors and their development as new anti-Chagas drugs.

A search of broader range of chemical space is important for drug discovery. Different methods of computer-aided drug discovery (CADD) are known to propose compounds in different chemical spaces as hit molecules for the same target protein. This study aimed at using multiple CADD methods through open innovation to achieve a level of hit molecule diversity that is not achievable with any particular single method. We held a compound proposal contest, in which multiple research groups participated and predicted inhibitors of tyrosine-protein kinase Yes. This showed whether collective knowledge based on individual approaches helped to obtain hit compounds from a broad range of chemical space and whether the contest-based approach was effective.

To ensure efficiency in discovery and development, the application of computational technology is essential. Although virtual screening techniques are widely applied in the early stages of drug discovery research, the computational methods used in lead optimization to improve activity and reduce the toxicity of compounds are still evolving. In this study, we propose a method to construct the residue interaction profile of the chemical structure used in the lead optimization by performing “inverse” mixed-solvent molecular dynamics (MSMD) simulation. Contrary to constructing a protein-based, atom interaction profile, we constructed a probe-based, protein residue interaction profile using MSMD trajectories. It provides us the profile of the preferred protein environments of probes without co-crystallized structures. We assessed the method using three probes: benzamidine, catechol, and benzene. As a result, the residue interaction profile of each probe obtained by MSMD was a reasonable physicochemical description of the general non-covalent interaction. Moreover, comparison with the X-ray structure containing each probe as a ligand shows that the map of the interaction profile matches the arrangement of amino acid residues in the X-ray structure.