A structure-based framework for selective inhibitor design and optimization.

Structure-based drug design aims to create active compounds with favorable properties by analyzing target structures. Recently, deep generative models have facilitated structure-specific molecular generation. However, many methods are limited by inadequate pharmaceutical data, resulting in suboptimal molecular properties and unstable conformations.

Machine learning insights into calcium phosphate nucleation and aggregation.

In this study, we utilized machine learning interatomic potentials (MLIPs) to investigate the nucleation mechanisms of calcium phosphate, a critical component of bone and teeth. Our analysis encompassed the process from pre-nucleation stage to the growth of amorphous calcium phosphate (ACP) in solution. We observed fluctuations in free calcium ion concentration and tracked the formation of uniform clusters in the early nucleation phases, confirming the existence of pre-nucleation clusters (PNCs).

Theoretical insights into enantioselective [2 + 1] cyclopropanation reactions of diazo compounds with electron-deficient olefins.

Context: The cyclopropane skeleton plays a significant role in bioactive  molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations.

Ambient hydrogenation of solid aromatics enabled by a high entropy alloy nanocatalyst.

Hydrogenation is a versatile chemical process with significant applications in various industries, including food production, petrochemical refining, pharmaceuticals, and hydrogen carriers/safety. Traditional hydrogenation of aromatics, hindered by the stable π-conjugated phenyl ring structures, typically requires high temperatures and pressures, making ambient hydrogenation a grand challenge. Herein, we introduce a PdPtRuCuNi high entropy alloy (HEA) nanocatalyst, achieving an exceptional 100% hydrogenation of carbon-carbon unsaturated bonds, including alkynyl and phenyl groups, in solid 1,4-bis(phenylethynyl)benzene (DEB) at 25 °C under ≤1 bar H and solventless condition.

Decarboxylation Mechanism of -Orotate Decarboxylase Revisited.

-Orotate decarboxylase (IDCase), which is involved in the thymidine salvage pathway, has attracted considerable interest owing to its chemical similarity to a hypothetical DNA decarboxylase in mammals. Although valuable insights into the active DNA demethylation of 5-methyl-cytosine can be obtained from the decarboxylation mechanism of 5-carboxyl-uracil (5caU) catalyzed by IDCase, this mechanism remains under debate. In this study, the catalytic mechanism of 5caU decarboxylation by IDCase was studied using hybrid quantum mechanics/molecular mechanics (QM/MM) methodologies and density functional theory (DFT) calculations with a truncated model.

A Three-Dimensional Open-Framework Tin(II) Sulfate with Near-Unity Photoluminescence Quantum Yield.

A new open-framework tin(II) sulfate, formulated as CHN·Sn(SO)·HO, was prepared under the structure-directing effect of piperazine. This compound features a 3D structure with 16-ring channels. Under ultraviolet light irradiation, it emits bright yellow luminescence with a near-unity photoluminescence quantum yield.

Self-assembly of rigid amphiphilic graft cyclic-brush copolymers to nanochannels using dissipative particle dynamics simulation.

The synthesis of specific artificial nanochannels remains a formidable challenge in the field of nanomaterials and synthetic chemistry. In particular, the preparation of artificial nanochannels using amphiphilic graft cyclic-brush copolymers (AGCCs) as monomers has garnered substantial attention. Nevertheless, because of the constrained time and length scales inherent in traditional molecular dynamics simulations, a comprehensive theoretical understanding of the morphological regulation mechanism governing the self-assembly of AGCCs into nanochannels remains elusive.

A theoretical study of the mechanism of cationic polymerization of isobutylene catalysed by EtAlCl/-BuCl with bis(2-chloroethyl)ether in hexanes.

The mechanism of cationic polymerization of isobutylene catalyzed by -BuCl/ethylaluminum dichloride (EADC) combined with bis(2-chloroethyl)ether (CEE) in -hexane solvent has been investigated using molecular dynamics (AIMD) and metadynamics (MTD) simulations. The results indicated that the polyisobutylene (PIB) initiation stage involves a clear two-step mechanism. Calculation of the free energy landscapes of the other two ether reactions reveals that the energy barriers of diisopropyl ether (i-PrO) and 2-chloroethyl ethyl ether (CEEE) are much higher than those of CEE, which is consistent with the experimental results.

Effects of void defects on the mechanical properties of biphasic calcium phosphate nanoparticles: A molecular dynamics investigation.

Porous biphasic calcium phosphate (BCP) ceramics are widely used in bone tissue engineering, and the mechanical properties of BCP implants must be reliable. However, the effects of pore structure (e.g.

Quantum Mechanical/Molecular Mechanical Elucidation of the Catalytic Mechanism of Leukotriene A4 Hydrolase as an Epoxidase.

Leukotriene A4 hydrolase (LTA4H) functions as a mono-zinc bifunctional enzyme with aminopeptidase and epoxidase activities. While the aminopeptidase mechanism is well understood, the epoxidase mechanism remains less clear. In continuation of our prior research, we undertook an in-depth exploration of the LTA4H catalytic role as an epoxidase, employing a combined SCC-DFTB/CHARMM method.

Discovery and Evaluation of 3-Quinoxalin Urea Derivatives as Potent, Selective, and Orally Available ATM Inhibitors Combined with Chemotherapy for the Treatment of Cancer via Goal-Oriented Molecule Generation and Virtual Screening.

ATM plays an important role in DNA damage response and is considered a potential target in cancer therapies. In this study, a goal-directed molecular generation approach based on ligand similarity and target specificity was applied to sample active molecules, and they were screened virtually to identify the theoretical lead compound , which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability .

Interactions between curcumin and human salt-induced kinase 3 elucidated from computational tools and experimental methods.

Natural products are widely used for treating mitochondrial dysfunction-related diseases and cancers. Curcumin, a well-known natural product, can be potentially used to treat cancer. Human salt-induced kinase 3 (SIK3) is one of the target proteins for curcumin.

Data Mining and Graph Network Deep Learning for Band Gap Prediction in Crystalline Borate Materials.

Crystalline borates are an important class of functional materials with wide applications in photocatalysis and laser technologies. Obtaining their band gap values in a timely and precise manner is a great challenge in material design due to the issues of computational accuracy and cost of first-principles methods. Although machine learning (ML) techniques have shown great successes in predicting the versatile properties of materials, their practicality is often limited by the data set quality.

Insights into the effect of protein glycosylation on carbohydrate substrate binding.

The role of glycosylation in the binding of glycoproteins to carbohydrate substrates has not been well understood. The present study addresses this knowledge gap by elucidating the links between the glycosylation patterns of a model glycoprotein, a Family 1 carbohydrate-binding module (TrCBM1), and the thermodynamic and structural properties of its binding to different carbohydrate substrates using isothermal titration calorimetry and computational simulation. The variations in glycosylation patterns cause a gradual transition of the binding to soluble cellohexaose from an entropy-driven process to an enthalpy-driven one, a trend closely correlated with the glycan-induced shift of the predominant binding force from hydrophobic interactions to hydrogen bonding.

Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors.

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively.

Identifying Protein-Ligand Interactions via a Novel Distance Self-Feedback Biomolecular Interaction Network.

Efficient and accurate characterizations of protein-ligand interactions are key to understanding biology at the molecular level. They are particularly useful in pharmaceutical industry applications. They are usually computationally demanding for those widely applied dynamics-based methods in identifying important residues or calculating ligand binding free energy.

Corrigendum to "Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics" [Bioact. Mater. 6 (2021) 2676-2687 / 452].

[This corrects the article DOI: 10.1016/j.bioactmat.

Processive binding mechanism of Cel9G from : molecular dynamics and free energy landscape investigations.

The degradation of recalcitrant polysaccharides such as cellulose and chitin requires the synergistic functionality of processive glycosidase (GH) cocktails. Understanding the fundamental phenomenon of processivity is of biological and economic importance for the conversion of biomass into biofuel. In this work, cellulase family 9 from (Cel9G), which is a processive endoglucanase, was used to elucidate the processive binding mechanism with respect to polysaccharides, since it exhibits a multimodular crystallographic structure.

Molecular Dynamics Simulation of Biomimetic Biphasic Calcium Phosphate Nanoparticles.

Biphasic calcium phosphate (BCP) is used as a bone substitute and bone tissue repair material due to its better control over bioactivity and biodegradability. It is crucial to stabilize the implanted biomaterial while promoting bone ingrowth. However, a lack of standard experimental and theoretical protocols to characterize the physicochemical properties of BCP limits the optimization of its composition and properties.

Molecular investigations of the prenucleation mechanism of bone-like apatite assisted by type I collagen nanofibrils: insights into intrafibrillar mineralization.

Bone is a typical inorganic-organic composite material with a multilevel hierarchical organization. In the lowest level of bone tissue, inorganic minerals, which are mainly composed of hydroxyapatite, are mineralized within the type I collagen fibril scaffold. Understanding the crystal prenucleation mechanism and growth of the inorganic phase is particularly important in the design and development of materials with biomimetic nanostructures.

Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond.

Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-β-carboline (PAC), a tubulin inhibitor, promotes selective degradation of αβ-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation.

Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib.

The kinase domain is highly conserved among protein kinases 'in terms of both sequence and structure. Conformational rearrangements of the kinase domain are affected by the phosphorylation of residues and the binding of kinase inhibitors. Interestingly, the conformational rearrangement of the active pocket plays an important role in kinase activity and can be used to design novel kinase inhibitors.

Exploring the Binding Mechanism of a Supramolecular Tweezer CLR01 to 14-3-3σ Protein Well-Tempered Metadynamics.

Using supramolecules for protein function regulation is an effective strategy in chemical biology and drug discovery. However, due to the presence of multiple binding sites on protein surfaces, protein function regulation selective binding of supramolecules is challenging. Recently, the functions of 14-3-3 proteins, which play an important role in regulating intracellular signaling pathways protein-protein interactions, have been modulated using a supramolecular tweezer, CLR01.

QM/MM investigation of the catalytic mechanism of processive endoglucanase Cel9G from .

Carbohydrate degradation catalyzed by glucoside hydrolases (GHs) is a major mechanism in biomass conversion. GH family 9 endoglucanase (Cel9G) from , a typical multimodular enzyme, contains a catalytic domain closely linked to a family 3c carbohydrate-binding module (CBM3c). Unlike the conventional behavior proposed for other carbohydrate-binding modules, CBM3c has a direct impact on catalytic activity.