Structural evolution-based ancestral sequence reconstruction of medium-chain alcohol dehydrogenase for efficient synthesis of fused-ring chiral alcohols.

On QSPR analysis for predicting efficacy of physicochemical properties of antibiotics drugs via topological indices and regression models.

• Neutron spectroscopy shows that the reorientational motions of the methyl groups in methacetin are highly sensitive to both temperature and pressure. • Analysis of the mean square displacement (MSD) reveals a clear deviation from the harmonic Debye model above 140-200 K. • DFT calculations demonstrate that in the crystalline state, methyl torsions are strongly coupled. • Quasi-elastic neutron scattering reveals that reorientational motion on the picosecond timescale is dominated by the O-CH₃ group. • Mixed C-CH₃ modes soften above 0.4 GPa, indicating reduced flexibility and increased rigidity under pressure. • Methacetin’s dynamic behaviour, influenced by subtle structural changes, highlights the importance of methyl group dynamics in pharmaceutical compounds. The dynamics of functional groups within drug molecules influences their medicinal or toxicological effects, with methyl groups’ conformational changes affecting binding to active sites. Here, we combine inelastic neutron scattering spectroscopy with density functional theory to investigate molecular dynamics and conformational flexibility of methacetin (C 9 H 11 NO 2 ), a member of the acetamide family that includes paracetamol (C 8 H 9 NO 2 ) and phenacetin (C 10 H 13 NO 2 ). Our results reveal that subtle variations in its crystal packing and hydrogen bonding lead to multiple conformations, with methyl group reorientations contributing significantly to the molecule’s dynamics. This study stresses the importance of integrating experimental and computational methods to understand the structural dynamics of pharmaceutical compounds and their implications for drug design.

Structurally similar, functionally different: Impact of coformer positional isomerism on co-amorphous enzalutamide.

The clinical application of the chemotherapeutic agent irinotecan is critically hindered by its low and variable solubility. To provide a fundamental understanding of this issue, we employed molecular dynamics simulations and free energy calculations to detail the solvation thermodynamics of irinotecan. Our analysis reveals that irinotecan's solvation preference is governed by a delicate and often competitive balance between two fundamental physical contributions: the Lennard-Jones term (representing cavity formation and dispersion) and favorable solute-solvent electrostatic interactions. We demonstrate that while polar protic solvents (e.g., water) provide the strongest electrostatic stabilization, their high energetic cost for cavity formation severely limits overall solvation favorability. Conversely, polar aprotic solvents (e.g., pyridine and DMSO) optimize this balance by facilitating easier cavity formation while still providing strong electrostatic interactions, resulting in the most favorable solvation profiles. Notably, irinotecan's unexpectedly high relative solubility in cyclohexane compared to water underscores the critical role of solvent reorganization energy in dictating solution-phase behavior. These molecular-level findings are rigorously validated by structural analyses (connection matrices and radial distribution functions) and a complementary macroscopic solubility parameter analysis (MOSCED framework). This study offers a robust, integrated, and predictive physicochemical framework for understanding and optimizing the formulation of complex, flexible drug molecules.

Click reactions that form functional linkages are rare. Among the few catalytic options, none directly delivers a cleavable connector. Here we introduce copper(I)-catalysed allene-ketone addition (CuAKA), an operationally simple reaction that is mutually orthogonal to CuAAC (copper(I)-catalysed azide-alkyne cycloaddition) and CuPDF (copper(I)-catalysed phenoxydiazaborinine formation). These three catalytic click strategies can be merged for efficient assembly of multifunctional entities. We show that CuAKA can be used to link an allene-bound drug molecule in aqueous media to a ketone-containing derivative of unprotected penetratin, a solubilizing and cell penetrating peptide. The viability of an allyl-metal complex runs counter to the long-held notion that C-C σ-bond formation and carbonyl addition are not suitable for click chemistry. We also show that CuAKA-generated linkages can be controllably cleaved (by rupturing a C-C bond) at 37 °C in a 68-86 μM solution of aqueous hydrogen peroxide. The advance underscores the versatility of functional click-generated connectors in biologically relevant environments.

A highly efficient copper‐catalyzed method has been developed for constructing valuable imidazo[1,2‐ f ]phenanthridinium derivatives from readily available imidazoles and torsionally strained cyclic diaryliodonium salts. Notably, this protocol is suitable for the late‐stage functionalization of imidazole motifs in complex drug molecules. Mechanistic studies indicate that the reaction proceeds via a tandem strain‐promoted ring‐opening/intramolecular cyclization sequence.

We report a facile, metal-free protocol for the direct amidation of readily available nitroarenes and carboxylic acids. The method proceeds via in situ activation of carboxylic acids, nitro-to-amine reduction, and subsequent C-N coupling to furnish the corresponding amide bond. This transformation exhibits broad functional group tolerance and delivers the desired amides in high yields. The method's applicability is showcased through the efficient synthesis of pharmaceutically and agrochemically important amide scaffolds and rapid derivatization of drug molecules containing carboxylic acid groups.

Structure-based virtual screening of the library of bioactive compounds was used to identify novel small-molecule compounds that can inhibit the catalytic activity of Mycobacterium tuberculosis (Mtb) enoyl acyl carrier protein reductase (InhA), one of the key enzymes involved in the biosynthesis of mycolic acids of the Mtb cell wall. To do this, we employed an integrated computational approach to drug repurposing which included high-throughput docking of the InhA enzyme with small-molecule compounds from the library of bioactive molecules containing the FDA-approved drugs and investigational drug candidates, molecular dynamics simulations of the ligand/InhA-NAD+ complexes, binding free energy calculations, post-modeling analysis followed by selection of the most promising drug candidates and experimental determination of their minimum inhibitory concentration MIC90. As a result, a lead compound which showed the MIC90 value of 62.5 µM against the vaccine strain Mycobacterium bovis and Mtb was found, giving hope that this compound forms a promising scaffold for the development of novel antitubercular molecules of clinical significance with activity against an important target of Mtb.

Structural basis of phosphodiesterase-5 conformational organization revealed by a PDE6/PDE5 Chimera.

Herein, we report an energy transfer (EnT)-mediated radical-relay Brook rearrangement starting from commercially available electron-deficient ketones and silanes. This method eliminates the need for pre-installed α-silyl groups by employing an engineered N-O reagent that mediates a cascade of silane activation, regioselective carbonyl addition, and radical-radical cross-coupling. The orchestrated radical-involved cascade sequence exhibits a broad substrate scope and excellent functional group tolerance. Moreover, this protocol enables the late-stage diversification of complex drug molecules, offering a new paradigm for photochemistry.

Deuteration has evolved into a transformative strategy in medicinal chemistry, materials science, and mechanistic research, owing to its ability to modulate molecular properties without perturbing core structures. As a privileged heterocyclic scaffold in natural products, pharmaceuticals, and functional materials, indole has become a prime target for deuteration. This review summarizes recent advances in regioselective indole deuteration, highlighting two core strategies: transition-metal-catalyzed hydrogen isotope exchange (HIE) (both directed and undirected) and non-metallic catalytic/chemical reagent-mediated methods. Key breakthroughs include site-selective labeling of challenging positions (such as C2 and C4) and late-stage deuteration of complex drug molecules, overcoming intrinsic reactivity biases of the indole ring. Despite these strides, critical challenges remain: limited regioselectivity for benzenoid ring (C4-C7) deuteration, functional group incompatibility, and practical barriers in cost-effective deuterium sources and scalability. Future directions focus on developing directing-group-free catalytic systems, integrating green strategies (electro/photocatalysis) with low-cost D2O, and expanding applications in pharmaceutical optimization and materials innovation. This review provides a comprehensive overview of the field, bridging synthetic innovation with translational potential.

Psoriasis is a chronic, immune-mediated disorder with strong genetic susceptibility and environmental triggers, characterized by excessive proliferation of keratinocytes and recruitment of inflammatory cells. Affecting 2-3% of the global population and represents a significant public health challenge. In psoriasis, the skin barrier is altered rather than uniformly enhanced, and its permeability varies with drug types and disease states, which may affect the effective delivery of drugs to affected areas. Nanotechnology demonstrates potential in drug delivery, protecting drug molecules from degradation, enabling targeted therapy, and reducing side effects, thereby improving pharmacokinetics and enhancing the bioavailability of therapeutic agents. This review specifically examines the emergence of multimodal nanotherapeutic approaches, which defined as the strategic integration of two or more distinct therapeutic modalities (e.g., pharmacotherapy paired with phototherapy, gene editing, or RNA interference) within a unified nanocarrier platform to achieve synergistic efficacy. By systematically evaluating these advanced combinatory strategies, this review provides a distinct perspective compared to existing literature, which predominantly focuses on conventional, single-mode drug delivery systems. To this end, it reviews nanotechnology combined with multiple therapies and introduces the current advantages and disadvantages of integrating nanotechnology with conventional anti-psoriatic drugs Finally, it presents the challenges and prospects of using nanotechnology to treat psoriasis and provides reliable solutions for its clinical management. Overall, this review advances psoriasis treatment toward precision and efficiency, revealing the broad prospects of nanomedicine in conquering this intractable disease.

Well-defined, small-molecule, platinum-centered coordination compounds are of continued interest in both basic and applied research, particularly in medicinal chemistry and pharmaceuticals (i.e., cisplatin). Organoplatinum(IV) complexes have been reported to exhibit substantial in vitro cytotoxicity across a range of cancer cell lines. Compared with coordinatively unsaturated platinum(II) species, electronically and coordinatively saturated platinum(IV) complexes are generally more inert, reducing undesirable side reactions in plasma and cellular environments and potentially improving their safety profiles as chemotherapeutic agents. In addition, the presence of organic ligands can enhance lipophilicity, facilitating passive diffusion across cell membranes. Here, we report the synthesis, structural characterization, and in vitro anticancer activity of a series of organoplatinum(IV) complexes of the general formula Pt(CH3)2I2{n,n′-dimethyl-2,2′-bipyridine} (n,n′ = 4,4′; 5,5′; 6,6′). The 5,5′- and 6,6′-dimethyl isomers were characterized by single-crystal X-ray diffraction. All three dimethyl-substituted complexes, along with the parent compound, Pt(CH3)2I2{2,2′-bipyridine}, were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines. Whereas Pt(CH3)2I2{2,2′-bipyridine} and the 4,4′- and 5,5′-dimethyl derivatives displayed limited cytotoxicity, the 6,6′-dimethyl isomer exhibited notable activity, particularly against the colon cancer cell line HCT-116 (LC50 = 8.17 μM) and the ovarian cancer cell line OVCAR-3 (LC50 = 7.34 μM). The enhanced cytotoxicity of the 6,6′-dimethyl derivative is attributed, at least in part, to the relatively facile dissociation of the 6,6′-dimethyl-2,2′-bipyridine ligand from the platinum(IV) center, suggesting that sterically induced ligand lability plays an important role in modulating biological activity in this particular compound, giving new structural activity impetus for potential drug molecules.

Automating structural optimization of drug molecules for on-target potency by machine learning is an open challenge in chemistry. Here, we capitalize on the ability of chemical language models (CLMs) to learn from sequential data and design new molecules with desired properties. We establish a training strategy mimicking the learning trajectory of a drug discovery program. Incremental CLM fine-tuning with increasingly potent template molecules from a given structure-activity relationship (SAR) series successfully biases the model to design highly active analogues. Prospective application of this technique to ligand development enables the data-driven design of molecules exceeding known representatives of given bioactive chemotypes in potency without external scoring. Our results reveal an ability of CLMs to capture SAR patterns and long-range dependencies, and to exploit SAR knowledge in designing analogues with improved on-target activity de novo corroborating their applicability to structural optimization of drug molecules.

Pharmaceutical contaminants such as aspirin (ASP), paracetamol (PAR), and ibuprofen (IBU) present increasing risks to environmental and human health, necessitating efficient detection and removal strategies. In this study, we performed a comprehensive first-principles investigation of their adsorption on a triquinoxalinylene and benzoquinone-based covalent organic framework (TQBQ-COF). The geometries were optimized and the adsorption complexes were characterized using density functional theory. The results reveal that all three drug molecules are effectively accommodated within the electron-rich central cavity of the COF, forming stable host-guest assemblies through van der Waals interactions while preserving the structural integrity of the framework. Frontier molecular orbital and global reactivity analyses indicate that drug adsorption, particularly for IBU, significantly reduces the HOMO-LUMO gap and chemical hardness, enhancing electronic sensitivity, reactivity, and charge-transfer capability. Electron density difference and non-covalent interaction analyses confirm directional electron flow from the drugs to the COF and identify stabilizing interactions governing adsorption. Simulated UV-Vis spectra show pronounced red-shifts upon drug adsorption, with the IBU@TQBQ-COF complex exhibiting the largest effect. Thermodynamic analyses further confirm spontaneous, exothermic adsorption dominated by enthalpy contributions. Collectively, these findings highlight TQBQ-COF as a highly sensitive and robust platform for drug detection and removal in aqueous and biologically relevant environments.

surfactants have shown promise in pharmaceutics addressing stability, toxicity, and drug solubility issues. However, developing effective medication delivery mechanisms is crucial. Our current study focuses on understanding the micellization behavior of Triton X-100, a surface-active ionic liquid (SAIL) in the presence of anti-inflammatory drug (NSAIDs). The study employs surface tension measurements to assess the micellization nature of the surfactant and drug mixture at various concentrations Viscosity properties of the mixed system are followed by viscosity techniques. Interaction between anionic surfactants and drugs. The results show a significant change in the CMC value with the rise in drug concentration, which depends on the nature of the drug. Triton X-100 (TX-100), a non-ionic surfactant, has been interacted with Ibuprofen drug characterized by 1 HNMR and FTIR spectroscopic techniques in the solid state. These artificially produced surfactants are effective in raising the solubility and bioavailability of drug molecules. Additional screening was done on surfactants to check for antibacterial and antifungal properties.

Skeletal editing has emerged as a powerful strategy for the late-stage diversification of drug molecules. Recently, transmutation of widely available pyridine motifs into less explored pyridazines via C-to-N single-atom swaps has garnered attention. Here, we report a CN-to-NN atom-pair swap to transmute pyridopyrimidones, dienamines that are generated by temporary dearomatization of pyridines, into pyridazines in a one- or two-pot dearomatization-[4 + 2]-retro-[4 + 2]-cycloaddition-aromatization sequence with 4-phenyl-1,2,4-triazoline-3,5-dione as the N═N dienophile. Crucially, this transformation only works with pyridopyrimidones and not with the previously established oxazinopyridine-based temporary dearomatization strategy; for the latter, the driving force for the retro-[4 + 2] cycloaddition is insufficient, since the formation of the target product itself does not facilitate a gain in arene resonance energy. Pyridopyrimidones provide such a driving force through the formation of an aromatic pyrimidone byproduct. The synthetic utility of the method is demonstrated through late-stage skeletal editing of complex molecules and a 7-mmol large-scale reaction.

We report a nickel-catalyzed cross-coupling reaction between oxime ester radical precursors and arylboronic acids that via a nitrogen-centered radical mechanism generates radicals from oxime esters. Using acyl, cyclobutanone, and benzyl oxime esters, this method successfully achieves the acylation, cyanoalkylation, and benzylation of arylboronic acids, demonstrating a broad scope. Notably, this strategy is applicable to the synthesis of the drug molecule fenofibrate and the bioactive molecule naphthylphenstatin, highlighting its potential utility for constructing complex bioactive molecules.

Halogenases offer valuable opportunities in synthetic chemistry and biocatalysis. Here, we identify two novel flavin-dependent phenolic multisite halogenases, FasVamrb99 and IdmB26, from distinct biosynthetic pathways that exhibit divergent polyhalogenation of naphthacemycin B2. Substrate screening revealed that both enzymes display robust polyhalogenation activity, enabling halogenation not only at ortho positions adjacent to nonphenolic hydroxyl groups but also across a range of drug molecules. These features highlight their versatility and potential as biocatalysts for synthetic applications.