From pixels to druggable leads: A CADD strategy for the design and synthesis of potent DDR1 inhibitors.

BACKGROUND AND OBJECTIVE: While numerous in silico tools exist for target-based drug discovery, the inconsistent integration of in vitro data with predictive models hinders research and development productivity. This is particularly apparent during the Hit-to-Lead stage, where unreliable in-silico tools often lead to suboptimal lead selection. Herein, we address this challenge by presenting a CADD-guided pipeline that successfully integrates rational drug design with in-silico hits to identify a promising DDR1 lead. METHODS: 2 × 1000 ns MD simulations along with their respective FEL and MMPBSA analyses were employed to guide the rational design and synthesis of 12 novel compounds which were evaluated for their DDR inhibition. RESULTS: The molecular dynamics investigation of the initial hit led to the identification of key structural features within the DDR1 binding pocket. The identified key features were used to guide the rational design and synthesis of twelve novel derivatives. SAR analysis, biological evaluation, molecular dynamics, and free energy calculations were carried out for the synthesized derivatives to understand their mechanism of action. Compound 4c exhibited the strongest inhibition and selectivity for DDR1, with an IC50 of 0.11 µM. CONCLUSIONS: The MD simulations led to the identification of a key hydrophobic groove in the DDR1 binding pocket. The integrated approach of SAR analysis with molecular dynamics led to the identification of compound 4c as a promising lead for further development of potent and selective DDR1 inhibitors. Moreover, this work establishes a protocol for translating in silico hits to real world bioactive druggable leads.

PT-Finder: A multi-modal neural network approach to target identification.

Efficient target identification for bioactive compounds, including novel synthetic analogs, is crucial for accelerating the drug discovery pipeline. However, the process of target identification presents significant challenges and is often expensive, which in turn can hinder the drug discovery efforts. To address these challenges machine learning applications have arisen as a promising approach for predicting the targets for novel chemical compounds. These methods allow the exploration of ligand-target interactions, uncovering of biochemical mechanisms, and the investigation of drug repurposing. Typically, the current target identification tools rely on assessing ligand structural similarities. Herein, a multi-modal neural network model was built using a library of proteins, their respective sequences, and active inhibitors. Subsequent validations showed the model to possess accuracy of 82 % and MPRAUC of 0.80. Leveraging the trained model, we developed PT-Finder (Protein Target Finder), a user-friendly offline application that is capable of predicting the target proteins for hundreds of compounds within a few seconds. This combination of offline operation, speed, and accuracy positions PT-Finder as a powerful tool to accelerate drug discovery workflows. PT-Finder and its source codes have been made freely accessible for download at https://github.com/PT-Finder/PT-Finder.

Fully Additively Manufactured Counter Electrodes for Dye-Sensitized Solar Cells.

In dye-sensitized solar cells (DSSCs), the counter electrode (CE) plays a crucial role as an electron transfer agent and regenerator of the redox couple. Unlike conventional CEs that are generally made of glass-based substrates (e.g., FTO/glass), polymer substrates appear to be emerging candidates, owing to their intrinsic properties of lightweight, high durability, and low cost. Despite great promise, current manufacturing methods of CEs on polymeric substrates suffer from serious limitations, including low conductivity, scalability, process complexity, and the need for dedicated vacuum equipment. In the present study, we employ and evaluate a fully additive manufacturing route that can enable the fabrication of CEs for DSSCs in a high-throughput and eco-friendly manner with improved performance. The proposed approach sequentially comprises: (1) material extrusion 3-D printing of polymer substrate; (2) conductive surface metallization through cold spray particle deposition; and (3) over-coating of a thin-layer catalyzer with a graphite pencil. The fabricated electrodes are characterized in terms of microstructure, electrical conductivity, and photo-conversion efficiency. Owing to its promising electrical conductivity (8.5 × 104 S·m-1) and micro-rough surface structure (Ra ≈ 6.32 µm), the DSSCs with the additively manufactured CEs led to ≈2.5-times-higher photo-conversion efficiency than that of traditional CEs made of FTO/glass. The results of the study suggest that the proposed additive manufacturing approach can advance the field of DSSCs by addressing the limitations of conventional CE manufacturing platforms.

Machine Learning-Based Approach to Developing Potent EGFR Inhibitors for Breast Cancer-Design, Synthesis, and In Vitro Evaluation.

The epidermal growth factor receptor (EGFR) is vital for regulating cellular functions, including cell division, migration, survival, apoptosis, angiogenesis, and cancer. EGFR overexpression is an ideal target for anticancer drug development as it is absent from normal tissues, marking it as tumor-specific. Unfortunately, the development of medication resistance limits the therapeutic efficacy of the currently approved EGFR inhibitors, indicating the need for further development. Herein, a machine learning-based application that predicts the bioactivity of novel EGFR inhibitors is presented. Clustering of the EGFR small-molecule inhibitor (∼9000 compounds) library showed that N-substituted quinazolin-4-amine-based compounds made up the largest cluster of EGFR inhibitors (∼2500 compounds). Taking advantage of this finding, rational drug design was used to design a novel series of 4-anilinoquinazoline-based EGFR inhibitors, which were first tested by the developed artificial intelligence application, and only the compounds which were predicted to be active were then chosen to be synthesized. This led to the synthesis of 18 novel compounds, which were subsequently evaluated for cytotoxicity and EGFR inhibitory activity. Among the tested compounds, compound 9 demonstrated the most potent antiproliferative activity, with 2.50 and 1.96 µM activity over MCF-7 and MDA-MB-231 cancer cell lines, respectively. Moreover, compound 9 displayed an EGFR inhibitory activity of 2.53 nM and promising apoptotic results, marking it a potential candidate for breast cancer therapy.

An Efficient Green Approach to Constructing Adenine Sulfate-Derived Multicolor Sulfur- and Nitrogen-Codoped Carbon Dots and Their Bioimaging Applications.

A cost-effective and environmentally friendly approach is proposed for producing N- and S-codoped multicolor-emission carbon dots (N- and S-codoped MCDs) at a mild reaction temperature (150 °C) and relatively short time (3 h). In this process, adenine sulfate acts as a novel precursor and doping agent, effectively reacting with other reagents such as citric acid, para-aminosalicylic acid, and ortho-phenylenediamine, even during solvent-free pyrolysis. The distinctive structures of reagents lead to the increased amount of graphitic nitrogen and sulfur doping in the N- and S-codoped MCDs. Notably, the obtained N- and S-codoped MCDs exhibit considerable fluorescence intensities, and their emission color can be adjusted from blue to yellow. The observed tunable photoluminescence can be attributed to variations in the surface state and the amount of N and S contents. Furthermore, due to the favorable optical properties, good water solubility and biocompatibility, and low cytotoxicity, these N- and S-codoped MCDs, especially green carbon dots, are successfully applied as fluorescent probes for bioimaging. The affordable and environmentally friendly synthesis method employed to create N- and S-codoped MCDs, combined with their remarkable optical properties, offers a promising avenue for their use in various fields, particularly in biomedical applications.

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library.

Cancer is characterized by altered cellular metabolism, and metabolic enzymes are considered as a promising target for anticancer therapy. Pyrimidine metabolism dysregulation is associated with various types of cancer, particularly lung cancer, which is one of the leading causes of cancer-related mortality worldwide. Recent studies have shown that small-cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and are sensitive to its disruption. DHODH, the rate-limiting enzyme of the de novo pyrimidine production pathway, is essential in the production of RNA and DNA and is overexpressed in malignancies such as AML, skin cancer, breast cancer, and lung cancer, thereby highlighting DHODH as a viable target for developing drugs to combat lung cancer. Herein, rational drug design and computational techniques were used to discover novel DHODH inhibitors. A small combinatorial library was generated, and the top hits were synthesized and tested for anticancer activity against three lung cancer cell lines. Among the tested compounds, compound 5c possessed a stronger cytotoxicity (TC50 of 11 µM) compared to the standard FDA-approved drug (Regorafenib, TC50 of 13 µM) on the A549 cell line. Furthermore, compound 5c demonstrated potent inhibitory activity against hDHODH at a nanomolar level of 421 nM. DFT, molecular docking, molecular dynamic simulations, and free energy calculations were also carried out to understand the inhibitory mechanisms of the synthesized scaffolds. These in silico studies identified key mechanisms and structural features that will be crucial for future studies.

Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure-Activity Relationships and Molecular Docking.

Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies.

c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2.Communicated by Ramaswamy H. Sarma.

Selective Deposition of Candle Soot on a Cellulose Membrane for Efficient Solar Evaporation.

Owing to their natural abundance, seawater together with sunlight has a potential to meet the global challenges in terms of water scarcity and energy crisis. Herein, we demonstrate a solar vapor generator composed of an inner flame candle soot (IFCS) deposited on a cellulose filter paper (FP) prepared by a simple two-step process. The resultant IFCS/FP device exhibits a high photothermal conversion ability owing to the broadband solar absorption of the IFCS layer along with the multiple scattering of the incoming sunlight in the porous microstructure of the cellulose FP. Additionally, the low thermal conductivity of the IFCS effectively localizes the photothermally generated heat at the IFCS/FP surface, thereby significantly suppressing the conduction heat losses to the underlying bulk water. Meanwhile, the capillary action of the FP supplies an adequate amount of water to the heated surface for accelerating the evaporation process. Benefitting from the synergistic effect of these characteristics, the IFCS/FP achieves high evaporation rates of ∼1.16 and ∼4.09 kg m-2 h-1 and their corresponding efficiencies of ∼75.1 and 90.9% under one and three sun illumination, respectively. Moreover, the IFCS/FP device presents an excellent longevity owing to the persistent performance over 15 repeated cycles under one and three sun illumination. Hence, the facile fabrication, fine mechanical strength, desalination, and the salt-resistance ability of our IFCS/FP make it a suitable candidate for practical applications.

Highly Efficient Solar Vapor Generation via a Simple Morphological Alteration of TiO2 Films Grown on a Glassy Carbon Foam.

Effectively utilizing eco-friendly solar energy for desalination and wastewater purification has immense potential to overcome the global water crisis. Herein, we demonstrate a highly efficient solar vapor generator (SVG) developed via a simple morphological alteration, from a two-dimensional (2D) TiO2 film (TF) to one-dimensional (1D) TiO2 nanorods (TNRs) grown on a glassy carbon foam (CF). Given that evaporation is primarily a surface physical phenomenon, the 1D morphology of TNRs provides a higher evaporation surface area compared to their 2D counterpart. Additionally, the superhydrophilic nature of TNRs ensures an adequate supply of water to the evaporation surface via effective capillary action. Consequently, the 1D TNRs properly utilize photothermal heat, which results in a significant reduction in the convection heat loss. Owing to the synergistic effect of these characteristics, TNRs/CF acquires a high evaporation rate of ∼2.23 kg m-2 h-1 and an energy utilization efficiency of ∼67.1% under one sun irradiation. Moreover, the excellent stability, desalination, self-cleaning capabilities, and the facile fabrication method make TNRs/CF suitable for cost-effective, large-scale device application.

Highly Efficient Solar Steam Generation by Glassy Carbon Foam Coated with Two-Dimensional Metal Chalcogenides.

Steam generation by eco-friendly solar energy has immense potential in terms of low-cost power generation, desalination, sanitization, and wastewater treatment. Herein, highly efficient steam generation in a bilayer solar steam generator (BSSG) is demonstrated, which is comprised of a large-area SnSe-SnSe2 layer deposited on a glassy carbon foam (CF). Both CF and SnSe-SnSe2 possess high photothermal conversion capabilities and low thermal conductivities. The combined bilayer system cumulatively converts input solar light into heat through phonon-assisted transitions in the indirect band gap SnSe-SnSe2 layer, together with trapping of sunlight via multiple scattering due to the porous morphology of the CF. This synergistic effect leads to efficient broadband solar absorption. Moreover, the low out-of-plane thermal conductivities of SnSe-SnSe2 and CF confine the generated heat at the evaporation surface, resulting in a significant reduction of heat losses. Additionally, the hydrophilic nature of the acid-treated CF offers effective water transport via capillary action, required for efficient solar steam generation in a floating form. A high evaporation rate (1.28 kg m-2 h-1) and efficiency (84.1%) are acquired under 1 sun irradiation. The BSSG system shows high recyclability, stability, and durability under repeated steam-generation cycles, which renders its practical device applications possible.

Nitrogen-Plasma-Treated Continuous Monolayer MoS2 for Improving Hydrogen Evolution Reaction.

Theoretically, the edges of a MoS2 flake and S-vacancy within the lattice have nearly zero Gibbs free energy for hydrogen adsorption, which is essentially correlated to the exchange currents in hydrogen evolution reaction (HER). However, MoS2 possesses insufficient active sites (edges and S-vacancies) in pristine form. Interestingly, active sites can be effectively engineered within the continuous MoS2 sheets by treating it with plasma in a controlled manner. Here, we employed N2 plasma on a large-area continuous-monolayer MoS2 synthesized via metal-organic chemical vapor deposition to acquire maximum active sites that are indeed required for an efficient HER performance. The MoS2 samples with maximum active sites were acquired by optimizing the plasma exposure time. The newly induced edges and S-vacancies were directly verified by high-resolution transmission electron microscopy. The 20 min treated MoS2 sample showed maximum active sites and thereby maximum HER activity, onset overpotential of ∼-210 mV vs reversible hydrogen electrode (RHE), and Tafel slope of ∼89 mV/dec. Clearly, the above results show that this approach can be employed for improving the HER efficiency of large-scale MoS2-based electrocatalysts.

Renoprotective effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, on rats with chronic kidney disease.

Chronic kidney disease (CKD) is a common cause of end-stage renal disease. Antihypertensive agents are used clinically to inhibit the progression of CKD, but cannot prevent eventual renal failure. This study investigated the effect of Tanshinone IIA, an active component of Salvia miltiorrhiza, in rats suffering from CKD induced by 5/6 nephrectomy. After development of renal insufficiency, the rats were treated with Tanshinone IIA (10 mg/kg) for 8 weeks. Serum creatinine, angiotensin II (Ang II), transforming growth factor ß1 (TGF-ß1) and collagen IV levels were significantly reduced in Tanshinone IIA treated rats compared with a control group. In addition, Tanshinone IIA suppressed increases in urinary protein excretion in CKD rats. These findings suggest that chronic oral administration of Tanshinone IIA can improve renal dysfunction associated with CKD.

Clinical and histologic response to methylprednisolone pulse therapy in glomerulonephritis.

We retrospectively analyzed the data of the first and second renal biopsies to investigate the adverse effects as well as the clinical and histologic responses of methylprednisolone pulse therapy in patients with chronic glomerulonephritis. At the time of the second renal biopsy, the activity index had decreased significantly and the chronicity index was well preserved. The activity index and interstitial fibrosis were improved in the complete and partial remission groups, but not in the nonresponse group. These findings indicate that methylprednisolone pulse therapy is effective in patients with chronic glomerulonephritis and has an acceptably low risk of side effects.

Linkage and association study of discoidin domain receptor 1 as a novel susceptibility gene for childhood IgA nephropathy.

In several experimental studies, it has been suggested that discoidin domain receptor 1 (DDR1) plays an important role in the regulation of mesangial proliferation, glomerular basement membrane thickening, renal fibrosis, and in the development of inflammation in several tissue types, including renal tissues. The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the DDR1 gene and childhood IgA nephropathy (IgAN). The genotyping data of 180 childhood IgAN patients and 336 controls showed significant differences in the frequency of rs1264319 (dominant model, P=0.040). Subgroup analysis revealed that development of proteinuria (>4 and

Polymorphisms of signal transducers and activators of transcription 1 and 4 (STAT1 and STAT4) contribute to progression of childhood IgA nephropathy.

BACKGROUND: Several experimental studies have suggested that signal transducers and activators of transcription 1 and 4 (STAT1 and STAT4) play important roles in the regulation of mesangial proliferation and renal fibrosis, and in the development of inflammation in several types of glomerulonephritis. METHODS: The present study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) of the STAT1 and STAT4 genes and childhood IgA nephropathy (IgAN). RESULTS: Genotyping of 170 childhood IgAN patients and 442 controls showed no significant differences in allele frequency. However, patient subgroup analysis revealed that development of proteinuria ( and >4mg/m(2)/h) was associated with STAT1 rs10199181 (dominant model, P=0.035) and high serum level of IgA with STAT1 rs6718902 (dominant model, P=0.035) and STAT1 rs2280232 (codominant model, P=0.014; dominant model, P=0.022). Furthermore, some SNP frequencies were significantly different between patients with pathologically mild and advanced disease; STAT1 rs6718902 (overdominant model, P=0.030), STAT1 rs10199181 (codominant model, P=0.023; dominant model, P=0.012; overdominant model, P=0.018), and STAT4 rs7561832 (dominant model, P=0.026; overdominant model, P=0.029). CONCLUSIONS: Our results suggest that polymorphisms of STAT1 and STAT4 are associated with increased susceptibility, pathological advancement, and development of proteinuria in childhood IgAN.

Effects of Bupleurum falcatum and its combination with an angiotensin II receptor blocker on cytokine and chemokine expression in human mesangial cells.

This study aimed to investigate the inhibitory effect of Bupleurum falcatum and its combination with angiotensin II receptor blocker (ARB) on cytokine and chemokine production in cultured human mesangial cells. Human mesangial cells were isolated and cultured in Dulbecco's modified Eagle's medium culture medium. Bupleurum falcatum, ARB, and the combination of the two were added to human mesangial cells. Cytokine and chemokine levels were analysed using an enzyme-linked immunosorbent assay. There were no significant differences in the expression of IL-1ss, IL-2 or TNF-a between controls and the experimental groups. However, IL-11 and monocyte chemoattractant protein-1 (MCP-1) levels were significantly reduced in response to ARB, Bupleurum falcatum, or their combination when compared with controls. IL-8 expression was reduced significantly only in cells treated with ARB. Both Bupleurum falcatum and ARB treatments alone reduced the cytokine concentration, but there was not a stronger reduction when the two drugs were combined. It was shown that Bupleurum falcatum inhibited cytokine production in human mesangial cells. However, there were no additive effects on the suppression of cytokine production when Bupleurum falcatum was combined with ARB. Further studies are needed to elucidate the renoprotective effects of Bupleurum falcatum.