Metal ions carry out a wide variety of functions, including acid-base/redox catalysis, structural functions, signaling, and electron transport. Understanding the interactions of transition metal complexes with biomacromolecules is essential for biology, medicinal chemistry, and the production of synthetic metalloenzymes. After the coincidental discovery of cisplatin, importance of the metal complexes in biochemistry became a top priority for inquiry. In this review, a decade update on various synthetic strategies to first row transition metal complex and their interaction with DNA through non-covalent binding are explored. Moreover, this effort provides an excellent analysis on the efficacy of theoretical and practical approaches to the systematic generation of new non-platinum based metallodrugs for anti-cancer therapeutics.

Adding polyphenols to improve the absorption of functional proteins has become a hot topic. Chlorogenic acid is a natural plant polyphenol with anti-inflammatory, antioxidant, and anticancer properties. Bovine lactoferrin is known for its immunomodulatory, anticancer, antibacterial, and iron-chelating properties. Therefore, the non-covalent binding of chlorogenic acid (CA) and bovine lactoferrin (BLF) with different concentrations under neutral conditions was studied. CA was grafted onto lactoferrin molecules by laccase catalysis, free radical grafting, and alkali treatment. The formation mechanism of non-covalent and covalent complexes of CA-BLF was analyzed by experimental test and theoretical prediction. Compared with the control BLF, the secondary structure of BLF in the non-covalent complex was rearranged and unfolded to provide more active sites, the tertiary structure of the covalent conjugate was changed, and the amino group of the protein participated in the covalent reaction. After adding CA, the covalent conjugates have better functional activity. These lactoferrin-polyphenol couplings can carry various bioactive compounds to create milk-based delivery systems for encapsulation.

Although Warburg discovered pH discrepancies between tumor and normal tissues nearly 100 years ago, developing therapies to take advantage of this concept was relatively slow for the first 70 years. During the last 30 years, there has been an exponential increase in the use of pH-dependent strategies for both low molecular weight drugs and nanoparticles. Two frequently discussed approaches are the chemotherapy\'s release from pH-sensitive covalent linkages of macromolecules or from pH-dependent disruption of charged polymeric nanoparticles. In contrast, pH-dependent non-covalent bonds between the chemotherapy agent and macromolecules have rarely been discussed, yet this underappreciated strategy has great potential. These non-covalent interactions are primarily ionic or hydrogen bonds with supporting roles from hydrophobic bonds. In addition to the facile coupling of the drug with the carrier, these non-covalent interactions may show marked pH dependence. Consistent with pH dependence, many of these drug-loaded carriers showed significant in vitro and, in some cases, striking in vivo activity. In this review, we will focus on pH-sensitive non-covalent bonds, highlighting the release of drugs from diverse carriers such as tetrahedron DNA structures, cyclodextrin, polymeric carriers, and carbon-based quantum particles.

OBJECTIVE: To provide a comprehensive review of the pharmacokinetics, pharmacodynamics, safety, and efficacy of a new Food and Drug Administration (FDA) approved Bruton\'s tyrosine kinase inhibitor (BTKi), pirtobrutinib for relapsed/refractory mantle cell lymphoma (r/r MCL).
METHODS: A literature search was conducted through PubMed MEDLINE, ClinicalTrials.gov, and the FDA website (January 2018-January 2023) using the following key terms: lymphoma, non-covalent, Bruton\'s tyrosine kinase (BTK), and relapse. Relevant English language monographs, studies, and abstracts conducted in humans were reviewed and considered.
METHODS: Pirtobrutinib, a novel non-covalent BTKi, was granted accelerated approval for treatment of r/r MCL on January 27th, 2023, based on an open-label, multi-center phase 1/2 BRUIN trial. In phase l, 61 patients with r/r MCL received seven dose levels of pirtobrutinib (25-300 mg). There was no reported maximum tolerated dose or dose-limiting toxicities during this study period. In phase 2, 56 r/r MCL evaluable efficacy patients received pirtobrutinib 200 mg daily. The overall response rate (ORR) was 52% (95% CI 38-65). Additionally, patients who received a previous covalent BTKi, ORR was 52% (95% CI 38-66). Neutropenia was the most common adverse reaction reported as a grade 3 or higher.
CONCLUSIONS: Pirtobrutinib has demonstrated safety and efficacy in heavily pre-treated adult patients with r/r MCL. Advantages of this drug include its usage in patients whose malignancy is resistant to current BTKi, tolerability, and response rate. Multiple clinical trials are underway to determine the efficacy of pirtobrutinib in other B-cell malignancies.

Potentially significant drug candidates often face elimination from consideration due to the lack of an effective method for systemic delivery. The poor solubility of these candidates has posed a major obstacle for their development as oral pills or injectables. Niclosamide, a host-directed antiviral, is a good example. In this study, a nanoformulation technology that allows for the non-covalent formulation of niclosamide with cholic acids was developed. This formulation enables efficient systemic delivery through endocytosis and enterohepatic circulation of bile-acid-coated nanoparticles. The oral bioavailability of niclosamide-delivery nanoparticles (NDNs) was significantly enhanced to 38.3%, representing an eight-fold increase compared with pure niclosamide. Consequently, the plasma concentration of niclosamide for the NDN formulation reached 1179.6 ng/mL, which is 11 times higher than the therapeutic plasma level. This substantial increase in plasma level contributed to the complete resolution of clinical symptoms in animals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This nanoformulation not only provides an orally deliverable antiviral drug for SARS-CoV-2 with improved pharmaceutical bioavailability, but also offers a solution to the systemic delivery challenges faced by potentially significant drug candidates.

Polyphenols have widely accepted health benefits which are limited by their low uptake, low bioavailability, and rapid degradation in the gut. While milk proteins are excellent carriers for polyphenols, the specific interactions of the polyphenols with the milk proteins, need to be understood to facilitate the utilization of these delivery systems in food and pharmaceutical applications. We have evaluated the relevance of different factors affecting milk protein-polyphenol interactions and the subsequent impact on the bioavailability and health promoting aspects of polyphenols. Hydrophobic forces are the primary binding forces of polyphenols to milk proteins. The significant factors affecting the interactions and binding affinity are the molecular weight and the hydrophobicity of the polyphenols. The interaction of polyphenols with milk proteins improved the antioxidant activity in comparison to milk proteins, while conflicting results exists for comparisons with polyphenols. In-vitro and cell line studies demonstrated enhanced bioavailability of polyphenols in the presence of milk proteins as well as higher anti-cancer and anti-allergy benefits. Overall, this work will pave the way for better understanding of polyphenol interactions with milk proteins and enable the tailoring of complexes through sustainable green processes, enabling higher bioavailability and health promoting effects of the polyphenols in food and pharmaceutical applications.

The development of antibacterial medications has recently been promoted due to the non- effective usage of antibiotics and the rise in severe bacterial infections. The effectiveness of antimicrobial therapy alternatives is constrained due to the prevalence of germs that are resistant to medications. Our current study\'s goal is to favor metallic compounds for antibiotic delivery in order to increase the effectiveness of the antibacterial regimen. Due to its bioactivity, potassium succinate-succinic acid is preferred because in general, the succinic acid compound has the greatest potential against microbial infections and a natural antibiotic because of its relative acidic nature. In the current study, the molecular geometry, band gap energies, molecular electrostatic interactions and potential energy distribution of the molecule were compared with those of certain succinate derivatives. The potential compound potassium succinate succinic acid was probed using FT-IR and FT-Raman analyses. Vibrational assignments pertaining to different modes of vibration with potential energy distribution have been improved by normal coordinate analysis. The chemical bond stability which is largely important for biological activity is studied using NBO analysis. The molecular docking study suggests that the molecule possesses antibacterial action and displays a minimal binding energy of -5.3 kcal/mol which can be endorsed for the prevention of any bacterial illness. From the results of our studies, the material would be stable and bioactive according to the FMO study, which indicates a band gap value of 4.35 eV and the pharmacokinetic features of the molecule, was predicted using the ADMET factors and the drug-likeness test.Communicated by Ramaswamy H. Sarma.

Using metal substrates that are nanoscale in size, surface-enhanced Raman scattering (SERS) is a technique for enhancing the Raman signal of biomolecules. Numerous industries including sensing materials, adsorption and medical devices, use nanomaterials like nanocages and nanoclusters. To discover a possible novel sensor platform involving a small metal cluster and a curved rigid substrate, we used density functional theoretical (DFT) simulations to explore the adsorption of glycoluril (GLC), a prospective drug intermediate, on a pure magnesium oxide cage (Mg12O12). This well defined cage was used as (i) an exact probable structure that could be used as well as (ii) a general model for MgO nanostructures. We also investigated the mono Al-doped Mg12O12 nanocage version Mg11AlO12. All computations were performed at the M06-2X level of theory. The GLC binds to the Mg12O12 nanocage by way of strong donor-acceptor interactions. The adsorption is releasing - 45.80 kcal mol-1 of energy. Due to Al doping, the energy gap of GLC-Mg11AlO12 (1.91 eV) is reduced from that of GLC-Mg12O12 (4.28 eV) and hence there is an increase in electrical conductivity of GLC-Mg11AlO12. The electronic change in the nanocage\'s conductivity can be transformed into an electrical signal which can be used to detect the presence of the drug analyte. In addition, when a GLC molecule is present, the work function of the nanocage is also reduced. The MgO nanocage, we conclude, is a work function type as well as a possible electronic sensor for GLC drug detection. GLC desorption from the Mg11AlO12 surface recovers more quickly in comparison with Mg12O12 recovery time. The AIM and NCIs assessed in this study were performed to help analyze the electronic structures of the complexes. Our findings pave the possibility for Mg11AlO12 nanostructures to be used in drug recognition.

The naturally occurring coumarin osthole has antipruritic properties, and recent reports suggest that this effect is due an inhibition or desensitization of the cation channels TRPV1 and TRPV3. Osthole was also suggested to activate TRPA1, an effect that should rather be pruritic than antipruritic. Here we characterized the effects of osthole on TRPA1 by means of ratiometric calcium imaging and patch clamp electrophysiology. In HEK 293 expressing human (h) TRPA1, osthole induced a concentration-dependent increase in intracellular calcium that was inhibited by the TRPA1-inhibitor A967079. In mouse dorsal root ganglion (DRG) cells, osthole induced a strong calcium-influx that was partly mediated by TRPA1. Osthole evoked fully reversible membrane currents in whole-cell as well as cell-free inside-out recordings on hTRPA1. Osthole failed to activate the mutant hTRPA1-S873V/T874L, a previously described binding site for the non-electrophilic TRPA1-agonists menthol and carvacrol. The combined application of osthole and carvacrol diminished channel activation, suggesting a competitive binding. Finally, osthole failed to activate TRPM8 and TRPV4 but induced a modest activation of hTRPV1 expressed in HEK 293 cells. We conclude that osthole is a potent non-electrophilic agonist of TRPA1. The relevance of this property for the antipruritic effects needs to be further explored.

The objective of this paper was to investigate the interactions between (-)-Epigallocatechin-3-gallate (EGCG) and whey protein isolate (WPI) by covalent and non-covalent combinations and the effects of the interactions on the conformational and functional changes of whey protein. Conformational changes in the secondary structure of whey protein with various concentrations of EGCG were studied using FTIR spectra. EGCG was more likely to form covalent bonds than non-covalent bonds when it interacted with whey proteins. The addition of EGCG altered the conformation of whey protein. The content of β-sheet decreased, while that of β-turn increased, however, the random coil remained unchanged. An reduction in surface hydrophobicity was observed in all the WPI-EGCG complexes, suggesting that modification in secondary structure of WPI were induced by EGCG. Additionally, the emulsifying and foaming attributes of WPI were enhanced after interaction with EGCG. This study confirms that EGCG can enhance the functional properties of WPI. It is also a pointer to the possible application of WPI-EGCG complexes in the dairy industry.