Structure and catalytic activity of a dihydrofolate reductase-like enzyme from Leptospira interrogans.

A dihydrofolate reductase (DHFR)-like enzyme from Leptospira interrogans (LiDHFRL) was cloned and the recombinant protein was characterized. Sequence alignment suggested that the enzyme lacked the conserved catalytic residues found in DHFR. Indeed, LiDHFRL did not catalyze the reduction of dihydrofolate by either NADH or NADPH.

Exploring mimosamycin as a Janus kinase 2 inhibitor: A combined computational and experimental investigation.

Janus kinases (JAKs) are a family of intracellular tyrosine kinases that play a crucial role in signal transduction pathways. JAK2 has been implicated in the pathogenesis of leukemia, making it a promising target for research aimed at reducing the risk of this disease. This study examined the potential of mimosamycin as a JAK2 inhibitor using both in vitro and in silico approaches.

Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice.

The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body's primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1).

Experimental and Computational Studies on Domain-Swapped Structure Stabilization of an Antibody Light Chain by Disulfide Bond Introduction.

Development of different platforms would be useful for designing functional antibodies to improve the efficiency of antibody-based drugs. Three-dimensional domain swapping (3D-DS) may occur in the variable region of antibody light chain #4C214A, and a pair of domain-swapped dimers may interact with each other to form a tetramer. In this study, to stabilize the 3D-DS dimer structure in #4C214A, Val2 in strand A (swapping region) and Thr97 in strand G were replaced with Cys residues, generating #4 V2C/T97C/C214A with a Cys2-Cys97 disulfide bond that cross-links strands A and G of different protomers.

Enantioselective interactions of aminonitrile dimers.

Enantioenrichment of amino acids is essential during the early chemical evolution leading to the origin of life. However, the detailed molecular mechanisms remain unsolved. Dimerization of enantiomers is the first molecular process in the nucleation of deposition and crystallization, which are both essential for enantioenrichment.

GPNMB is a novel binding partner of FGFR1 that affects tumorigenic potential through AKT phosphorylation in TNBC.

Breast cancer is a heterogeneous disease and is one of the most prevalent cancers in women. Triple-negative breast cancer (TNBC) is a relatively aggressive subtype of breast cancer, which is difficult to treat. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein that is overexpressed in various types of cancers, including breast cancer, especially TNBC.

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors.

Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1' and P2', to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity.

Enzymatic Cleavage of Double-Stranded DNA-Encoded Libraries (DELs) to Single-Stranded DELs with Compounds at the 3' End: Its Application in Photo-Crosslinking Selection.

DNA-encoded library (DEL) technology is a crucial tool in pharmaceutical research, rapidly identifying compounds that bind to a target of interest from an extensive pool of compounds. In this study, we propose a new method for generating single-stranded DELs (ssDELs) with compounds at the 3' end. The introduction of uniquely designed hairpin-shaped headpieces containing deoxyuridine (NC-HP) and the use of a cleavage enzyme facilitate the conversion from double-stranded DELs (dsDELs) to such ssDELs.

BEMM-GEN: A Toolkit for Generating a Biomolecular Environment-Mimicking Model for Molecular Dynamics Simulation.

Understanding the influence of the cellular environment on protein conformations is crucial for elucidating protein functions within living cells. In studies using molecular dynamics (MD) simulation, carbon nanotubes and hydrophobic cages have been widely used to emulate the cellular environment inside specific large biomolecules such as ribosome tunnels and chaperones. However, recent studies suggest that these uniform hydrophobic models may not adequately capture the environmental effects inside each biomolecule.

Rational Design of Cyclopentadiene-Based Super- and Hyperacids Based on Aromaticity.

The design and synthesis of neutral organic superacids have been of interest recently due to their vast applications in chemistry and material sciences, for example, olefinic polymerization, isolation of highly reactive short-lived cations, etc. Cyclopentadiene behaves as a mild organic acid, producing a stable conjugate base by gaining aromaticity and conjugation after deprotonation. To stabilize conjugate bases of organic acids to show superacidities and hyperacidities, we considered aromatic phenyl substituents with cyclopentadiene (mono-, di-, and triphenyl-substituted cyclopentadiene and their cyano derivatives).

Ribosome Tunnel Environment Drives the Formation of α-Helix during Cotranslational Folding.

Protein conformations in cells are not solely determined by amino acid sequences; they also depend on cellular environments. For instance, the ribosome tunnel induces its specific α-helix formation during cotranslational folding. Owing to the link between these temporally α-helix and biological functions, the mechanism of α-helix formation inside the ribosome tunnel has been previously explored.

Calcium Binding Mechanism in TAT Rhodopsin.

TAT rhodopsin binds Ca near the Schiff base region, which accompanies deprotonation of the Schiff base. This paper reports the Ca-free and Ca-bound structures of TAT rhodopsin by molecular dynamics (MD) simulation launched from AlphaFold structures. In the Ca-bound TAT rhodopsin, Ca is directly coordinated by eight oxygen atoms, four oxygens of the side chains of E54 and D227, and four oxygens of water molecules.

Real-time observation of a metal complex-driven reaction intermediate using a porous protein crystal and serial femtosecond crystallography.

Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales.

Machine learning-based QSAR and LB-PaCS-MD guided design of SARS-CoV-2 main protease inhibitors.

The global outbreak of the COVID-19 pandemic caused by the SARS-CoV-2 virus had led to profound respiratory health implications. This study focused on designing organoselenium-based inhibitors targeting the SARS-CoV-2 main protease (M). The ligand-binding pathway sampling method based on parallel cascade selection molecular dynamics (LB-PaCS-MD) simulations was employed to elucidate plausible paths and conformations of ebselen, a synthetic organoselenium drug, within the M catalytic site.

Aggregation of Apo/Glycated Human Serum Albumins and Aptamer-Saturated Graphene Quantum Dot: A Simulation Study.

Human serum albumin (HSA) is a protein carrier that transports a wide range of drugs and nutrients. The amount of glycated HSA (GHSA) is used as a diabetes biomarker. To quantify the GHSA amount, the fluorescent graphene-based aptasensor has been a successful method.

Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various β-cyclodextrin derivatives using advanced computational techniques and experimental validation.

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with β-cyclodextrin (βCD) and its three analogs, dimethyl-β-cyclodextrin (DMβCD), hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobutylether-β-cyclodextrin (SBEβCD), were investigated using in silico and in vitro studies.

Alpha and gamma mangostins inhibit wild-type B SARS-CoV-2 more effectively than the SARS-CoV-2 variants and the major target is unlikely the 3C-like protease.

Background: Anti-SARS-CoV-2 and immunomodulatory drugs are important for treating clinically severe patients with respiratory distress symptoms. Alpha- and gamma-mangostins (AM and GM) were previously reported as potential 3C-like protease (3CL) and Angiotensin-converting enzyme receptor 2 (ACE2)-binding inhibitors .

Objective: We aimed to evaluate two active compounds, AM and GM, from for their antivirals against SARS-CoV-2 in live virus culture systems and their cytotoxicities using standard methods.

Prediction of the binding mechanism of a selective DNA methyltransferase 3A inhibitor by molecular simulation.

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.

Network topology diversification of porous organic salts.

Hydrogen-bonded organic frameworks (HOFs) are porous organic materials constructed hydrogen bonds. HOFs have solubility in specific high-polar organic solvents. Therefore, HOFs can be returned to their components and can be reconstructed, which indicates their high recyclability.

Site Identification and Next Choice Protocol for Hit-to-Lead Optimization.

Time efficiency and cost savings are major challenges in drug discovery and development. In this process, the hit-to-lead stage is expected to improve efficiency because it primarily exploits the trial-and-error approach of medicinal chemists. This study proposes a site identification and next choice (SINCHO) protocol to improve the hit-to-lead efficiency.

Preferential Door for Ligand Binding and Unbinding Pathways in Inhibited Human Acetylcholinesterase.

Rising global population and increased food demands have resulted in the increased use of organophosphate pesticides (OPs), leading to toxin accumulation and transmission to humans. Pralidoxime (2-PAM), an FDA-approved drug, serves as an antidote for OP therapy. However, the atomic-level detoxification mechanisms regarding the design of novel antidotes remain unclear.

Cocrystalline Matrices for Hyperpolarization at Room Temperature Using Photoexcited Electrons.

We propose using cocrystals as effective polarization matrices for triplet dynamic nuclear polarization (DNP) at room temperature. The polarization source can be uniformly doped into cocrystals formed through acid-acid, amide-amide, and acid-amide synthons. The dense-packing crystal structures, facilitated by multiple hydrogen bonding and π-π interactions, result in extended relaxation times, enabling efficient polarization diffusion within the crystals.