Integrated computational approaches for advancing antimicrobial peptide development.

The increasing prevalence of antimicrobial resistance has intensified the need for novel antimicrobial drugs. Antimicrobial peptides (AMPs) are promising alternative antibiotics due to their broad-spectrum activity and slower resistance development. However, the time-consuming, costly development and challenge of systematic optimization limit their translation into the clinic.

AI-Powered Mining of Highly Customized and Superior ESIPT-Based Fluorescent Probes.

Excited-state intramolecular proton transfer (ESIPT) has attracted great attention in fluorescent sensors and luminescent materials due to its unique photobiological and photochemical features. However, the current structures are far from meeting the specific demands for ESIPT molecules in different scenarios; the try-and-error development method is labor-intensive and costly. Therefore, it is imperative to devise novel approaches for the exploration of promising ESIPT fluorophores.

Rational Design of Organelle-Targeted Fluorescent Probes: Insights from Artificial Intelligence.

Monitoring the physiological changes of organelles is essential for understanding the local biological information of cells and for improving the diagnosis and therapy of diseases. Currently, fluorescent probes are considered as the most powerful tools for imaging and have been widely applied in biomedical fields. However, the expected targeting effects of these probes are often inconsistent with the real experiments.

Molecular Mechanisms of Mercury-Sensitive Aquaporins.

Aquaporins are transmembrane channels that allow for the passive permeation of water and other small molecules across biological membranes. Their channel activities are sensitive to mercury ions. Intriguingly, while most aquaporins are inhibited by mercury ions, several aquaporins are activated by mercury ions.

Dynamic Interactions Between Brilliant Green and MscL Investigated by Solid-State NMR Spectroscopy and Molecular Dynamics Simulations.

The mechanosensitive ion channel of large conductance (MscL) is a promising template for the development of new antibiotics due to its high conservation and uniqueness to microbes. Brilliant green (BG), a triarylmethane dye, has been identified as a new antibiotic targeted MscL. However, the detailed binding sites to MscL and the dynamic pathway of BG through the MscL channel remain unknown.

Mechanism of unusual AQP6 activation by mercury binding to a pore-external residue C155.

Aquaporins (AQPs) transport water molecules across cell membranes. Although most aquaporins are inhibited by mercury ions, AQP6 was reported to be activated by binding mercury ions to residues C155 and C190. Different from C190 and the other pore-line cysteine residues, C155 is located outside the pore, thus not directly affecting the internal pathway by mercury binding to it.

Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches.

Limited circulating tumor cells (CTCs) capturing efficiency and lack of regulation capability on CTC-supportive metastatic niches (MNs) are two main obstacles hampering the clinical translation of conventional liposomes for the treatment of metastatic breast cancers. Traditional delivery strategies, such as ligand modification and immune modulator co-encapsulation for nanocarriers, are inefficient and laborious. Here, a multifunctional Rg3 liposome loading with docetaxel (Rg3-Lp/DTX) was developed, in which Rg3 was proved to intersperse in the phospholipid bilayer and exposed its glycosyl on the liposome surface.

Molecular docking-based computational platform for high-throughput virtual screening.

Structure-based virtual screening is a key, routine computational method in computer-aided drug design. Such screening can be used to identify potentially highly active compounds, to speed up the progress of novel drug design. Molecular docking-based virtual screening can help find active compounds from large ligand databases by identifying the binding affinities between receptors and ligands.

Perspective of drug design with high-performance computing.

The representative applications, recent advances and possible future directions of computational drug design were summarized, aiming to accelerate the drug discovery with the assistance of the fast-developing high-performance computing.

Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study.

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm.

Molecular simulation studies of the interactions between the human/pangolin/cat/bat ACE2 and the receptor binding domain of the SARS-CoV-2 spike protein.

The recent outbreak of SARS-CoV-2 has had a profound effect on the world. Similar to that in SARS-CoV, the entry receptor of SARS-CoV-2 is ACE2. The binding of SARS-CoV-2 spike protein to ACE2 is the critical to the virus infection.

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19.

Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients.

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China.

Protein encapsulation: a new approach for improving the capability of small-molecule fluorogenic probes.

Herein, we report a protein-based hybridization strategy that exploits the host-guest chemistry of HSA (human serum albumin) to solubilize the otherwise cell impermeable ONOO fluorescent probe . Formation of a / supramolecular hybrid was confirmed by SAXS and solution-state analyses. This / hybrid provided an enhanced fluorescence response towards ONOO alone, as determined by experiments.

Structural Mechanism of Barriers to Interspecies Seeding Transmissibility of Full-Length Prion Protein Amyloid.

A puzzling feature of prion diseases is the cross-species barriers. The detailed molecular mechanisms underlying these interspecies barriers remain poorly understood because of a lack of high-resolution structural information on the scrapie isoform of the prion protein (PrP ). In this study we identified the critical role of the residues 165/167 in the barrier to seeding mouse PrP (mPrP) fibril seeds to human cellular prion protein (PrP ).

Structural Insight into the Mechanism of Staphylococcus aureus Stp1 Phosphatase.

Staphylococcus aureus Stp1, which belongs to the bacterial metal-dependent protein phosphatase (PPM) family, is a promising candidate for antivirulence targeting. How Stp1 recognizes the phosphorylated peptide remains unclear, however. In order to investigate the recognition mechanism of Stp1 in depth, we have determined a series of crystal structures of S.

The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations.

Serine/threonine phosphatase (Stp1) is a member of the bacterial Mg- or Mn- dependent protein phosphatase/protein phosphatase 2C family, which is involved in the regulation of Staphylococcus aureus virulence. Aurintricarboxylic acid (ATA) is a known Stp1 inhibitor with an IC50 of 1.03 μM, but its inhibitory mechanism has not been elucidated in detail because the Stp1-ATA cocrystal structure has not been determined thus far.

Sensitive Water-Soluble Fluorescent Probe Based on Umpolung and Aggregation-Induced Emission Strategies for Selective Detection of Hg in Living Cells and Zebrafish.

Using Hg-induced umpolung reaction and aggregation induced emission (AIE), we have rationally developed a water-soluble fluorescent probe 2,2'-(((4-(4,5-bis(4-methoxyphenyl)-1-phenyl-1H-imidazol-2-yl)phenyl)methylene)bis(sulfanediyl))diethanol (MPIPBS) for Hg detection. MPIPBS was found to have high selectivity and sensitivity toward Hg detection. The mechanism of MPIPBS response to Hg was verified by H NMR titration, HPLC, and HRMS spectroscopy.

Biochemical Studies and Molecular Dynamic Simulations Reveal the Molecular Basis of Conformational Changes in DNA Methyltransferase-1.

DNA methyltransferase-1 (DNMT1) plays a crucial role in the maintenance of genomic methylation patterns. The crystal structure of DNMT1 was determined in two different states in which the helix that follows the catalytic loop was either kinked (designated helix-kinked) or well folded (designated helix-straight state). Here, we show that the proper structural transition between these two states is required for DNMT1 activity.

Structural insights into the potency of SK channel positive modulators.

Small-conductance Ca-activated K (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin.

Conformation and dynamics of the C-terminal region in human phosphoglycerate mutase 1.

Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle.

Discovery of novel trimethoxy-ring BRD4 bromodomain inhibitors: AlphaScreen assay, crystallography and cell-based assay.

As a member of the bromodomain and extra terminal domain (BET) protein family, BRD4 is closely related to cancers and other diseases. Small-molecule BRD4 inhibitors have already demonstrated promising potential for the therapy of BRD4-related cancers. In this study, we report the discovery and evaluation of a novel category of BRD4 inhibitors, which share a trimethoxy ring and target the first bromodomain of the human BRD4 protein.

Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus.

Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase 'WalK' (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus.

Applying high-performance computing in drug discovery and molecular simulation.

In recent decades, high-performance computing (HPC) technologies and supercomputers in China have significantly advanced, resulting in remarkable achievements. Computational drug discovery and design, which is based on HPC and combines pharmaceutical chemistry and computational biology, has become a critical approach in drug research and development and is financially supported by the Chinese government. This approach has yielded a series of new algorithms in drug design, as well as new software and databases.