Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence.

Understanding protein sequence and structure is essential for understanding protein-protein interactions (PPIs), which are essential for many biological processes and diseases. Targeting protein binding hot spots, which regulate signaling and growth, with rational drug design is promising. Rational drug design uses structural data and computational tools to study protein binding sites and protein interfaces to design inhibitors that can change these interactions, thereby potentially leading to therapeutic approaches. Artificial intelligence (AI), such as machine learning (ML) and deep learning (DL), has advanced drug discovery and design by providing computational resources and methods. Quantum chemistry is essential for drug reactivity, toxicology, drug screening, and quantitative structure-activity relationship (QSAR) properties. This review discusses the methodologies and challenges of identifying and characterizing hot spots and binding sites. It also explores the strategies and applications of artificial-intelligence-based rational drug design technologies that target proteins and protein-protein interaction (PPI) binding hot spots. It provides valuable insights for drug design with therapeutic implications. We have also demonstrated the pathological conditions of heat shock protein 27 (HSP27) and matrix metallopoproteinases (MMP2 and MMP9) and designed inhibitors of these proteins using the drug discovery paradigm in a case study on the discovery of drug molecules for cancer treatment. Additionally, the implications of benzothiazole derivatives for anticancer drug design and discovery are deliberated.

Nitrogen and sulphur doped carbon dot: An excellent biocompatible candidate for in-vitro cancer cell imaging and beyond.

Carbon dots (CDs) are an exquisite class of carbon allotrope that is already well nourished for their good biocompatibility, water-solubility, excellent photostability, and magnificent photoluminescence property. Doping strategy with heteroatoms is an efficacious way to modify the physicochemical and optical properties, making the carbon dots an exceedingly potential candidate. This work reports the fabrication and cancer cell imaging application of photoluminescent heteroatom-doped carbon dots by use of cysteine and urea as carbon, nitrogen, and sulphur sources through a straightforward and highly productive hydrothermal procedure. The fabricated luminescent carbon dots are spherical in shape, with an average diameter of 3.5 nm. X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) characterization revealed key facts about the surface functional groups and chemical compositions of carbon dots. The excitation-dependent photoluminescence (PL) peak appeared at around 445 nm against the excited wavelength of 350 nm. Moreover, under the provided experimental conditions, all the carbon dots are non-toxic and safe. The cytotoxicity and the safety profiles of the carbon dots were found to be in the bearable range under normal in-vitro experimental circumstances. Cellular uptake was observed by the green fluorescence of carbon dots inside cells. Likewise, the carbon dots did not alter the cell viability of the normal glial cell line. Again, when treated with the carbon dots, there was no notable increase of apoptotic cells in the G2/M phase of cell cycle analysis that confirmed the imaging-trackable ability of the carbon dots.

Carbon Dots for Multiuse Platform: Intracellular pH Sensing and Complementary Intensified T1-T2 Dual Imaging Contrast Nanoprobes.

Measurement of pH in living cells is a great and decisive factor for providing an early and accurate diagnosis factor. Along with this, the multimodal transverse and longitudinal relaxivity enhancement potentiality over single modality within a single platform in the magnetic resonance imaging (MRI) field is a very challenging issue for diagnostic purposes in the biomedical field of application. Therefore, this work aims to design a versatile platform by fabricating a novel nanoprobe through holmium- and manganese-ion doping in carbon quantum dots (Ho-Mn-CQDs), which can show nearly neutral intracellular pH sensing and MRI imaging at the same time. These manufactured Ho-Mn-CQDs acted as excellent pH sensors in the near-neutral range (4.01-8.01) with the linearity between 6.01 and 8.01, which could be useful for the intracellular pH-sensing capability. An innumerable number of carboxyl and amino groups are present on the surface of the prepared nanoprobe, making it an excellent candidate for pH sensing through fluorescence intensity quenching phenomena. Cellular uptake and cell viability experiments were also executed to affirm the intracellular accepting ability of Ho-Mn-CQDs. Furthermore, with this pH-sensing quality, these Ho-Mn-CQDs are also capable of acting as T1-T2 dual modal imaging contrast agents in comparison with pristine Ho-doped and Mn-doped CQDs. The Ho-Mn-CQDs showed an increment of r1 and r2 relaxivity values simultaneously compared with only the negative contrast agent, holmium in holmium-doped CQDs, and the positive contrast agent, manganese in manganese-doped CQDs. The above-mentioned observations elucidate that its tiny size, excitation dependence of fluorescence behavior, low cytotoxicity, and dual modal contrast imaging capability make it an ideal candidate for pH monitoring in the near-neutral range and also as a dual modal MRI imaging contrast enhancement nanoprobe at the same time.

Dynamic Metal-Coordinated Adhesive and Self-Healable Antifreezing Hydrogels for Strain Sensing, Flexible Supercapacitors, and EMI Shielding Applications.

Dynamic metal-coordinated adhesive and self-healable hydrogel materials have garnered significant attention in recent years due to their potential applications in various fields. These hydrogels can form reversible metal-ligand bonds, resulting in a network structure that can be easily broken and reformed, leading to self-healing capabilities. In addition, these hydrogels possess excellent mechanical strength and flexibility, making them suitable for strain-sensing applications. In this work, we have developed a mechanically robust, highly stretchable, self-healing, and adhesive hydrogel by incorporating Ca2+-dicarboxylate dynamic metal-ligand cross-links in combination with low density chemical cross-links into a poly(acrylamide-co-maleic acid) copolymer structure. Utilizing the reversible nature of the Ca2+-dicarboxylate bond, the hydrogel exhibited a tensile strength of up to ∼250 kPa and was able to stretch to 15-16 times its original length. The hydrogel exhibited a high fracture energy of ∼1500 J m-2, similar to that of cartilage. Furthermore, the hydrogel showed good recovery, fatigue resistance, and fast self-healing properties due to the reversible Ca2+-dicarboxylate cross-links. The presence of Ca2+ resulted in a highly conductive hydrogel, which was utilized to design a flexible resistive strain sensor. This hydrogel can strongly adhere to different substrates, making it advantageous for applications in flexible electronic devices. When adhered to human body parts, the hydrogel can efficiently detect limb movements. The hydrogel also exhibited excellent performance as a solid electrolyte for flexible supercapacitors, with a capacitance of ∼260 F/g at 0.5 A/g current density. Due to its antifreezing and antidehydration properties, this hydrogel retains its flexibility at subzero temperatures for an extended period. Additionally, the porous network and high water content of the hydrogel impart remarkable electromagnetic attenuation properties, with a value of ∼38 dB in the 14.5-20.5 GHz frequency range, which is higher than any other hydrogel without conducting fillers. Overall, the hydrogel reported in this study exhibits diverse applications as a strain sensor, solid electrolyte for flexible supercapacitors, and efficient material for electromagnetic attenuation. Its multifunctional properties make it a promising candidate for use in various fields as a state-of-the-art material.

Lysine-Mediated Yttrium Oxide Nanoparticle-Incorporated Nanofibrous Scaffolds with Tunable Cell Adhesion, Proliferation, and Antimicrobial Potency for In Vitro Wound-Healing Applications.

The intricate healing mechanism of chronic wounds and their multitude of healing-related obstacles, such as infections, compromised cellular processes, and impediments to the healing process, pose a significant healthcare problem. Exploration of metal oxide nanoparticles, such as yttrium oxide (Y2O3) nanoparticles, can lead to innovative discoveries in the field of chronic wound healing by offering cues that promote cell proliferation in the scaffolds. To achieve this, Y2O3 nanoparticles were synthesized and incorporated within poly(vinyl alcohol) (PVA) nanofibrous scaffolds. Moreover, lysine was infused in the nanofibrous scaffolds to tune its cell adhesion and antimicrobial property. The structure and morphology of the synthesized nanofibers were confirmed through various physicochemical characterizations. Notably, all the fabricated scaffolds have remarkably tuned WVTR values within the range of 2000-2500 g/m2/day, favorable for removing the wound exudate, which facilitate the healing process. The scaffolds exhibited substantial antimicrobial property of approximately 68% and 72.2% against both E. coli and S. aureus at optimized Y2O3 loading. They further prevented the formation of biofilm by 68.6% for S. aureus and 51.2% for P. aeruginosa, suggesting the inhibition of recurrent wound infection. The scaffolds illustrated good blood biocompatibility, cytocompatibility, and cell adhesion capabilities. In vitro ROS inhibition study also corroborated the antioxidant property of the scaffold. Similarly, the wound scratching experiment showed high proliferative capability of a yttria-loaded PVA/lysine (S3) sample through the development of an extracellular matrix support. Molecular insight of wound healing was also validated through flow cytometry analysis and immunocytochemistry imaging studies. The findings revealed increased collagen I (Col-I) expression of approximately 19.48% in cultured fibrocytes. The findings are validated from immunocytochemistry imaging. In summary, the results furnish a captivating paradigm for the use of these scaffolds as a therapeutic biomaterial and to foster their potential efficacy toward wound care management.

Magnolol and Temozolomide exhibit a synergistic anti-glioma activity through MGMT inhibition.

Temozolomide (TMZ) is the leading chemotherapeutic agent used for glioma therapy due to its good oral absorption and blood-brain barrier permeability. However, its anti-glioma efficacy may be limited due to its adverse effects and resistance development. O6-Methylguanine-DNA-methyltransferase (MGMT), an enzyme associated with TMZ resistance, is activated via the NF-κB pathway, which is found to be upregulated in glioma. TMZ also upregulates NF-κB signaling like many other alkylating agents. Magnolol (MGN), a natural anti-cancer agent, has been reported to inhibit NF-κB signaling in multiple myeloma, cholangiocarcinoma, and hepatocellular carcinoma. MGN has already shown promising results in anti-glioma therapy. However, the synergistic action of TMZ and MGN has not been explored. Therefore, we investigated the effect of TMZ and MGN treatment in glioma and observed their synergistic pro-apoptotic action in both in vitro and in vivo glioma models. To explore the mechanism of this synergistic action, we found that MGN inhibits MGMT enzyme both in vitro and in vivo glioma. Next, we established the link between NF-κB signaling and MGN-induced MGMT inhibition in glioma. MGN inhibits the phosphorylation of p65, a subunit of NF-κB, and its nuclear translocation to block NF-κB pathway activation in glioma. MGN-induced NF-κB inhibition results in the transcriptional inhibition of MGMT in glioma. TMZ and MGN combinatorial treatment also impedes p65 nuclear translocation to inhibit MGMT in glioma. We observed a similar effect of TMZ and MGN treatment in the rodent glioma model. Thus, we concluded that MGN potentiates TMZ-induced apoptosis in glioma by inhibiting NF-κB pathway-mediated MGMT activation.

Fabrication of a Vitamin B12-Loaded Carbon Dot/Mixed-Ligand Metal Organic Framework Encapsulated within the Gelatin Microsphere for pH Sensing and In Vitro Wound Healing Assessment.

Bacterial invasion is a serious concern during the wound healing process. The colonization of bacteria is mainly responsible for the pH fluctuation at the wound site. Therefore, the fabrication of a proper wound dressing material with antibacterial activity and pH monitoring ability is necessary to acquire a fast healing process. Therefore, this work is dedicated to designing a vitamin B12-loaded gelatin microsphere (MS) decorated with a carbon dot (CD) metal-organic framework (MOF) for simultaneous pH sensing and advanced wound closure application. The resultant MS portrayed a high specific surface area and a hierarchically porous structure. Furthermore, the surface of the resultant MS contained numerous carboxyl groups and amine groups whose deprotonation and protonation with the pH alternation are accountable for the pH-sensitive properties. The vitamin B12 release study was speedy from the MOF structure in an acidic medium, which was checked by gelatin coating, and a controlled drug release behavior was observed. The system showed excellent cytocompatibility toward the L929 cell line and remarkable antibacterial performance against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Furthermore, the combined effect of Zn2+, the imidazole unit, and CDs produces an outstanding bactericidal effect on the injury sites. Finally, the in vitro wound model suggests that the presence of the vitamin B12-loaded gelatin MS accelerates the proliferation of resident fibroblast L929 cells and causes tissue regeneration in a time-dependent manner. The relative wound area, % of wound closure, and wound healing speed values are remarkable and suggest the requirement for assessing the response of the system before exploiting its prospective in vivo application.