Accurate protein-ligand binding free energy estimation using QM/MM on multi-conformers predicted from classical mining minima.

Accurate prediction of binding free energy is crucial for the rational design of drug candidates and understanding protein-ligand interactions. To address this, we have developed four protocols that combine QM/MM calculations and the mining minima (M2) method, tested on 9 targets and 203 ligands. Our protocols carry out free energy processing with or without conformational search on the selected conformers obtained from M2 calculations, where their force field atomic charge parameters are substituted with those obtained from a QM/MM calculation.

1,2,4-trihydroxybenzene induces non-apoptotic cell death via the structural damage of intracellular organelles.

Benzene occurs naturally and is widely applied in the production process of petrochemical products. It is mainly exposed through the respiratory tract and dermal and metabolized in the liver, leading to systemic health effects, and 1,2,4-trihydroxybenzene (THB) is a benzene metabolite used as a hair dye ingredient in some countries. In an effort to identify a toxic mechanism of THB, we first analyzed the hair of consumers who used a shampoo containing THB, and contrary to our expectations, THB was not persistent in the hair.

Photocatalytic Conversion of CO to Formate/CO by an (η--Cymene)Ru(II) Half-Metallocene Catalyst: Influence of Additives and TiO Immobilization on the Catalytic Mechanism and Product Selectivity.

The catalytic efficacy of the monobipyridyl (η--Cymene)Ru(II) half-metallocene, [(-Cym)Ru(bpy)Cl] was evaluated in both mixed homogeneous (dye + catalyst) and heterogeneous hybrid systems (dye/TiO/Catalyst) for photochemical CO reduction. A series of homogeneous photolysis experiments revealed that the (-Cym)Ru(II) catalyst engages in two competitive routes for CO reduction (CO to formate conversion via Ru-hydride vs CO to CO conversion through a Ru-COOH intermediate). The conversion activity and product selectivity were notably impacted by the p value and the concentration of the proton source added.

Perfluorooctanoic acid inhibits cell proliferation through mitochondrial damage.

Grown evidence has shown that the liver and reproductive organs were the main target organs of perfluorooctanoic acid (PFOA). Herein, we studied a toxic mechanism of PFOA using HeLa Chang liver epithelial cells. When incubated with PFOA for 24 h or 48 h, cell proliferation was inhibited in a concentration- and time-dependent fashion, but interestingly, the feature of dead cells was not notable.

Elucidating TH301's influence on the torsion angle of CRY1 W399 using replica exchange with solute tempering (REST) molecular dynamics (MD) simulations.

Cryptochrome 1 (CRY1) is a protein involved in the circadian clock and associated with various diseases. Targeting CRY1 for drug development requires the discovery of competitive inhibitors that target its FAD binding site through ubiquitination. During the development of compounds to regulate CRY1, an intriguing compound called TH301 was identified.

Comparison of disinfectants-induced gene expression profile: Potential adverse effects.

Despite their importance in combating the spread of the COVID-19 pandemic, adverse effects of disinfectants on human health, especially the respiratory system, have been of continuing concern to researchers. Considering that bronchi are the main target of sprayed disinfectants, we here treated the seven major active ingredients in disinfectant products accepted by the US EPA to human bronchial epithelial cells and determined the subtoxic levels. Then, we performed microarray analysis using total RNA obtained at the subtoxic level and designed a network representing disinfectant-induced cellular response using the KEGG pathway analysis technique.

Combining QM/MM Calculations with Classical Mining Minima to Predict Protein-Ligand Binding Free Energy.

We developed an effective binding free energy prediction protocol which incorporates quantum mechanical/molecular mechanical (QM/MM) calculations to substitute the specified atomic charges of force fields with quantum-mechanically recalculated ones at a proposed pose using a mining minima approach with the VeraChem mining minima engine. We tested this protocol using seven well-known targets with 147 different ligands and compared it with classical mining minima and the most popular binding free energy (BFE) methods using different metrics. Our new protocol, dubbed Qcharge-VM2, yielded an overall Pearson correlation of 0.

High-temperature adaptation of an allele is thermoregulated by small RNAs.

Climate change negatively affects crop yield, which hinders efforts to reach agricultural sustainability and food security. Here, we show that a previously unidentified allele of the nitrate transporter gene is required to maintain high yield and high nitrogen use efficiency under high temperatures. We demonstrate that this tolerance to high temperatures in rice accessions harboring the HTNE-2 (high temperature resistant and nitrogen efficient-2) alleles from enhanced translation of the mRNA isoform and the decreased abundance of a unique small RNA (sNRT2.

Sensitization of GSH synthesis by curcumin curtails acrolein-induced alveolar epithelial apoptosis via Keap1 cysteine conjugation: A randomized controlled trial and experimental animal model of pneumonitis.

Introduction: Epidemiological studies have reported an association between exposures to ambient air pollution and respiratory diseases, including chronic obstructive pulmonary disease (COPD). Pneumonitis is a critical driving factor of COPD and exposure to air pollutants (e.g.

Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails.

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor potently inhibited Lck kinase with great selectivity (IC of 23.

Effect of Structural Fine-Tuning on Chelate Stability and Liver Uptake of Anionic MRI Contrast Agents.

The purpose of this study is to assess the physicochemical properties and MRI diagnostic efficacy of two newly synthesized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd chelates, Gd-SucL and Gd-GluL, with an asymmetric α-substituted pendant arm as potential hepatocyte-specific magnetic resonance imaging contrast agents (MRI CAs). Our findings show that fine conformational changes in the chelating arm affect the pharmacokinetic behavior of the MRI CA, and that a six-membered chelating substituent of Gd-SucL is more advantageous in this system to avoid unwanted interactions with endogenous species. Gd-SucL exhibited a general DOTA-like chelate stability trend, indicating that all chelating arms retain coordination bonding.

Rare Missense Functional Variants at and in Sporadic Intracerebral Hemorrhage.

Objective: To test the genetic contribution of rare missense variants in and in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.

Methods: We performed sequencing across 559 Kbp at 13q34 including and among 2,133 individuals (1,055 ICH cases; 1,078 controls) in United States-based and 1,381 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.

Results: We identified 107 rare nonsynonymous variants in sporadic ICH, of which 2 missense variants, rs138269346 (COL4A1) and rs201716258 (COL4A2), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the United States-based cohort.

pH-promoted O-α-glucosylation of flavonoids using an engineered α-glucosidase mutant.

Retaining glycosidase mutants lacking its general acid/base catalytic residue are originally termed thioglycoligases which synthesize thio-linked disaccharides using sugar acceptor bearing a nucleophilic thiol group. A few thioglycoligases derived from retaining α-glycosidases have been classified into a new class of catalysts, O-glycoligases which transfer sugar moiety to a hydroxy group of sugar acceptors, resulting in the formation of O-linked glycosides or oligosaccharides. In this study, an efficient O-α-glucosylation of flavonoids was developed using an O-α-glycoligase derived from a thermostable α-glucosidase from Sulfolobus solfataricus (MalA-D416A).

Target-Specific Drug Design Method Combining Deep Learning and Water Pharmacophore.

Following identification of a target protein, hit identification, which finds small organic molecules that bind to the target, is an important first step of a structure-based drug design project. In this study, we demonstrate a target-specific drug design method that can autonomously generate a series of target-favorable compounds. This method utilizes the seq2seq model based on a deep learning algorithm and a water pharmacophore.

Elucidation of Mechanism for Ligand Efficacy at Leukotriene B Receptor 2 (BLT2).

G protein-coupled receptors (GPCRs) have always been important drug targets in the pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies at the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies at Leukotriene B receptor (BLT2).

Gadolinium-Based Neuroprognostic Magnetic Resonance Imaging Agents Suppress COX-2 for Prevention of Reperfusion Injury after Stroke.

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke.

Influence of alkyl chain substitution of ammonium ionic liquids on the activity and stability of tobacco etch virus protease.

Ionic liquids (ILs) are known to provide stability to biomolecules. ILs are also widely used in the fields of chemical engineering, biological engineering, chemistry, and biochemistry because they facilitate enzyme catalyzed reactions and enhance their conversion rate. In this work, we have evaluated the influence of alkyl chain substitution of ammonium ILs such as diethylammonium dihydrogen phosphate (DEAP) and triethylammonium hydrogen phosphate (TEAP) for the stability and activity of the tobacco etch virus (TEV) protease.

Highly brain-permeable apoferritin nanocage with high dysprosium loading capacity as a new T contrast agent for ultra-high field magnetic resonance imaging.

High sensitivity at ultra-high field (UHF) and sufficient potential to penetrate the brain are the most desirable characteristics in the development of contrast agents (CAs) for magnetic resonance imaging (MRI). However, incorporating such qualities into a single nanocarrier is challenging. Herein, we report a new strategy for a highly brain-permeable MR CA with high sensitivity at UHF by loading dysprosium chelates (DyL) in apoferritin cavities (Apo-DyL).

Elucidation of the inhibition mechanism of sulfiredoxin using molecular modeling and development of its inhibitors.

When intracellular reactive oxygen species (ROS) increase, cancer cells are more vulnerable to oxidative stress compared to normal cells; thus, the collapse of redox homeostasis can lead to selective death of cancer cells. Indeed, recent studies have shown that inhibition of sulfiredoxin (Srx), which participates in antioxidant mechanisms, induces ROS-mediated cancer cell death. In this paper, we describe how an Srx inhibitor, J14 (4-[[[4-[4-(2-chlor-ophenyl)-1-piperazinyl]-6-phenyl-2-pyrimidinyl]thio]methyl]-benzoic acid), interferes with the antioxidant activity of Srx at the molecular level.

Englerin A-sensing charged residues for transient receptor potential canonical 5 channel activation.

The transient receptor potential canonical (TRPC) 5 channel, known as a nonselective cation channel, has a crucial role in calcium influx. TRPC5 has been reported to be activated by muscarinic receptor activation and extracellular pH change and inhibited by the protein kinase C pathway. Recent studies have also suggested that TRPC5 is extracellularly activated by englerin A (EA), but the mechanism remains unclear.

Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis.

Ginsenoside Rd is a saponin from ginseng and has been reported to have various biological activities. However, the effect of ginsenoside Rd on the metastasis of colorectal cancer (CRC) remains unknown. Here, we found that ginsenoside Rd decreased the colony-forming ability, migration, invasion, and wound-healing abilities of CRC cells, although it did not affect cell proliferation.

Synthesis and Evaluation of Manganese(II)-Based Ethylenediaminetetraacetic Acid-Ethoxybenzyl Conjugate as a Highly Stable Hepatobiliary Magnetic Resonance Imaging Contrast Agent.

In this study, we designed and synthesized a highly stable manganese (Mn)-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd) chelates and evaluated its usage as a T hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r relaxivity (2.3 mM s) than clinically approved Mn-based hepatobiliary complex Mn-DPDP (1.

Exploring the Ligand Efficacy of Cannabinoid Receptor 1 (CB1) using Molecular Dynamics Simulations.

Cannabinoid receptor 1 (CB1) is a promising therapeutic target for a variety of disorders. Distinct efficacy profiles showed different therapeutic effects on CB1 dependent on three classes of ligands: agonists, antagonists, and inverse agonists. To discriminate the distinct efficacy profiles of the ligands, we carried out molecular dynamics (MD) simulations to identify the dynamic behaviors of inactive and active conformations of CB1 structures with the ligands.

Water Pharmacophore: Designing Ligands using Molecular Dynamics Simulations with Water.

In this study, we demonstrate a method to construct a water-based pharmacophore model which can be utilized in the absence of known ligands. This method utilizes waters found in the binding pocket, sampled through molecular dynamics. Screening of compound databases against this water-based pharmacophore model reveals that this approach can successfully identify known binders to a target protein.