Development of novel focal adhesion kinase (FAK) inhibitors for targeting cancer: Structural insights and therapeutic potential.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase frequently overexpressed in various cancer cells, facilitating tumor growth through the regulation of cell adhesion, migration, and proliferation. Consequently, targeting FAK is considered a promising anti-tumor strategy, particularly for invasive cancers. Numerous potent small-molecule inhibitors have progressed to clinical trials. Among these, Defactinib is under evaluation for regulatory approval as a treatment for ovarian serous tumors. Furthermore, novel FAK inhibitors, including PROTACs, have emerged as key research focuses, anticipated to overcome the limitations of traditional inhibitors. In this Perspective, we highlight the protein structure, biological functions, relevant signaling pathways, and associations of FAK with cancer development. We also analyze the clinical status of FAK inhibitors, paying special attention to the various classes of FAK inhibitors, with detailed analyses of their chemical structures, structure-activity relationships (SARs), bioactivity profiles, selectivity profiles, and therapeutic potentials.

Synthesis and characterization of new antimicrobial peptides derived from Temporin F.

Antimicrobial peptides (AMPs) are a promising source of new compounds against resistant bacteria. Temporins are a class of AMPs found on the amphibian Rana temporaria and show activity against Gram-positive and Gram-negative bacteria. There are few studies on how these antimicrobials have been used, but new Temporin-F derivatives were engineered with Lys-substitutions to assess the impact of the net charge on antimicrobial activity and toxicity. We demonstrated through some assays that it is possible to increase the antibacterial activity while maintaining a reduced peptide hemolytic activity with specific substitutions. Our lead synthetic peptide, G6K-Temporin F, has shown higher antimicrobial activity against Gram-negative and Gram-positive bacteria in vitro (MIC range 2 to 32 µmol L-1), with low hemolytic activity maintained, resulting in an increase in the therapeutic window (TW), of 12.5. Also, it showed more resistant to enzymatic degradation. On the other hand, more significant increases in net charges, such as in P3K-G11K-Temporin F, result in a severe increase in toxicity with lower gains in antimicrobial activity (TW of 0.65). In conclusion, we demonstrated that a moderate increase in net charge can lead to a more active analog and G6K-Temporin F is revealed to be promising as a candidate for new AMP therapeutics.

Structure Activity Optimization of Ryanodine Receptor Modulators for the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with potentially lethal arrhythmias. Most CPVT cases are caused by inherited variants in the ryanodine receptor type-2 (RYR2) gene. OBJECTIVE: To investigate the structure activity relationship of tetracaine derivatives and test a lead compound in a mouse model of CPVT. METHODS: We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested using confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested using programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed. RESULTS: Ca2+ imaging revealed that 4 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited an EC50 of 146 nM (MSV1302) and 49 nM (MSV1406), respectively. While neither compound altered baseline ECG intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively impact cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr, exhibited excellent stability in plasma and microsomes, and was not cytotoxic. CONCLUSION: Structure activity relationship studies of second generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.

Advances in microbial exopolysaccharides as α-amylase inhibitors: Effects, structure-activity relationships, and anti-diabetic effects in vivo.

The rapid digestion of starch, as the main source of energy in the human diet, causes an acute increase in blood sugar levels that will affect blood glucose homeostasis. The inhibition of α-amylase activity is an effective way of reducing starch digestibility, thereby controlling postprandial glycemia. As a class of carbohydrate polymers, microbial exopolysaccharides (EPSs) have garnered widespread attention for their inhibitory effects on α-amylase, but there is a lack of comprehensive review in this area. This paper aimed to review the inhibitory activity of microbial EPSs on α-amylase and their interaction mechanisms, and the effect of microbial EPSs on lowering blood glucose levels and regulating glycolipid metabolism in vivo were also discussed. Numerous studies have reported that EPSs with α-amylase inhibition activity are primarily produced by lactic acid bacteria. Microbial EPSs with an appropriate range of molecular weight, high proportion of glucose or mannose or arabinose residues, and high uronic acid content might be acceptable to inhibit α-amylase activity. Additionally, microbial EPSs exhibited potential anti-diabetic effects in mice, reducing blood glucose levels, and regulating glycolipid metabolism and gut microbiota. The information covered in this review may enhance the development and application of EPSs in functional food and pharmaceutical research.

Insight into the therapeutic potential of pyrazole-thiazole hybrids: A comprehensive review.

Several pyrazole-thiazole hybrids featuring two potentially bioactive pharmacophores with or without linker have been synthesized using the molecular hybridization approach as target structures by medicinal chemists to modulate multiple drug targets simultaneously. The presented review aims to provide an overview of the diversified and wide array of pharmacological activities of these hybrids bestowing anticancer, antifungal, antibacterial, analgesic, anti-inflammatory, antioxidant, antitubercular, antiviral, antiparasitic, and miscellaneous activities. The structure-activity relationships and potential mechanism of action are also reviewed to shed light on the development of more effective and biotargeted candidates. This review focuses on the latest research advances in the biological profile of pyrazole-thiazole hybrids reported from 2015 to the present, providing medicinal researchers with a comprehensive platform to rationally design and develop more promising pyrazole-thiazole hybrids.

Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: A critical review.

Pyrrolo[2,3-d]pyrimidine-based kinase inhibitors have emerged as an important class of targeted therapeutics to combat various types of cancer. The distinctive structural feature of pyrrolopyrimidine ring system offers an adaptable platform for designing potent inhibitors of various kinases, crucial in regulating cellular processes. The deazapurine framework inherent to pyrrolopyrimidines bears a conspicuous resemblance to adenine, the natural ligand ATP. The structural mimicry enhances their appeal as potent inhibitors of key kinases. This review reconnoitres the intricate process of designing and developing pyrrolopyrimidine based derivatives, accentuating their structural diversity and the strategic modifications employed to enhance selectivity, potency, and pharmacokinetic properties. The discussion delves into medicinal chemistry strategies, highlighting successful examples that have been progressed to clinical evaluation. Furthermore, the review highlights the promise of pyrrolopyrimidine scaffolds in revolutionizing targeted cancer therapy and provides a pioneering perspective on future directions.

Carbonic anhydrases: Moiety appended derivatives, medicinal and pharmacological implications.

In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure-activity relationships, biological evaluation, and in silico studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications.

Discovery of sp3-rich diazatricycloundecanes as lysosomotropic autophagy inhibitors.

We have discovered lysosomotropic autophagy inhibitors from our compound library of sp3-rich diazatricycloundecane skeletons. Compound 1u was identified as the most potent biological activity for LC3-II protein accumulation through the structure-activity relationships (SARs) for LC3-II protein accumulation and anti-proliferative activity at the three freely available substituents (R1-R3) in the diazatricycloundecane skeleton. Compound 1u inhibited lysosome-dependent degradation without affecting autophagosome formation. Furthermore, compound 1u enlarged lysosomes and raised lysosomal pH similar to lysosomotropic agents such as chloroquine, resulting in inhibiting late-stage autophagy by inducing lysosomal dysfunction. Moreover, compound 1u exhibits excellent drug-like chemical properties, not previously reported for lysosomotropic agents.

Breakthroughs in AI and multi-omics for cancer drug discovery: A review.

Cancer is one of the biggest medical challenges we face today. It is characterized by abnormal, uncontrolled growth of cells that can spread to different parts of the body. Cancer is extremely complex, with genetic variations and the ability to adapt and evolve. This means we must continuously pursue innovative approaches to developing new cancer drugs. While traditional drug discovery methods have led to important breakthroughs, they also have significant limitations that make it difficult to efficiently create new, cost-effective cancer therapies. Integrating computational tools into the cancer drug discovery process is a major step forward. By harnessing computing power, we can overcome some of the inherent barriers of traditional methods. This review examines the range of computational techniques now being used, such as molecular docking, QSAR models, virtual screening, and pharmacophore modeling. It looks at recent advances in areas like machine learning and molecular simulations. The review also discusses the current challenges with these technologies and envisions future directions, underscoring how transformative these computational tools can be for creating targeted, new cancer treatments.

The molecular design of novel phospholipid-inspired ionic liquid transdermal penetration enhancers: Innovative insights on the action mode and mechanism.

Ionic liquid transdermal penetration enhancers (IL@TPEs) as new enhancement methods have significant advantages in the transdermal drug delivery system. However, the scientific frameworks for the design of efficient IL@TPEs and their applications in transdermal formulations were still lack. So, a series of novel biomimetic phospholipid-inspired IL@TPEs (PIL@TPEs) were designed and synthesized. The developed QSARs proved that enhancement efficacy of PIL@TPEs depended on pKa of drugs and M.W., Polar., and pKa of cations. Surprisingly, the PIL@TPEs dissociated during transdermal process, and skin penetration amounts of acidic drugs was inversely proportional to skin retention amounts of cations, which showed that action modes of PIL@TPEs were different from conventional enhancers. The novel mechanisms of PIL@TPEs were elucidated by quantitative determination of dynamic interaction among cations, anions, drugs, and skins. The PIL@TPEs with high enhancement efficiency owned strong interactions with drugs determined by ATR-FTIR, Raman and NOESY. Moreover, the PIL@TPEs owning better stability in skin ensured the production of strong interactions with lipids and keratins characterized by ATR-FTIR, 1H NMR and CLSM. The good safety of optimized PIL@TPEs was proved by determining cytotoxicity, apoptosis, inflammatory cells, and cytokines. In conclusion, this project will make an important contribution to the design and application of IL@TPEs.

Insights into structure and activity of a UDP-GlcNAc 2-epimerase involved in secondary cell wall polymer biosynthesis in Paenibacillus alvei.

Introduction: S-layer anchoring in Paenibacillus alvei is enabled by a non-covalent interaction between an S-layer homology domain trimer and a secondary cell wall polymer (SCWP), ensuring the structural integrity of the bacterial cell wall. Within the SCWP repeat, pyruvylated ManNAc serves as the ligand and the UDP-GlcNAc-2-epimerase MnaA supplies UDP-ManNAc to SCWP biosynthesis. Methods: To better understand SCWP biosynthesis and identify strategies for inhibiting pathogens with comparable cell wall architecture, like Bacillus anthracis, MnaA and rational variants were produced in E. coli and their kinetic constants determined. The effect of UDP-GlcNAc as a predicted allosteric activator and tunicamycin as a potential inhibitor of MnaA was tested in vitro supported by molecular docking experiments. Additionally, wild-type MnaA was crystallized. Results: We present the crystal structure of unliganded P. alvei MnaA resolved at 2.20 Å. It adopts a GT-B fold consistent with other bacterial non-hydrolyzing UDP-GlcNAc 2-epimerases. A comparison of amino acid sequences reveals conservation of putative and known catalytic and allosteric-site residues in MnaA, which was confirmed through analysis of Q42A, Q69A, E135A and H241A MnaA variants. The kinetic parameters K M and k cat of MnaA were determined to be 3.91 mM and 33.44 s-1 for the forward, and 2.41 mM and 6.02 s-1 for the reverse reaction. While allosteric regulation by UDP-GlcNAc has been proposed as a mechanism for enzyme activation, UDP-GlcNAc was not found to be essential for UDP-ManNAc epimerization by P. alvei MnaA. However, the reaction rate doubled upon addition of 5% UDP-GlcNAc. Unexpectedly, the UDP-GlcNAc analog tunicamycin did not inhibit MnaA. Molecular docking experiments comparing tunicamycin binding of P. alvei MnaA and Staphylococcus aureus MnaA, which is inhibited by tunicamycin, revealed different residues exposed to the antibiotic excluding, those at the predicted allosteric site of P. alvei MnaA, corroborating tunicamycin resistance. Conclusion: The unliganded crystal structure of P. alvei MnaA reveals an open conformation characterized by an accessible cleft between the N- and C-terminal domains. Despite the conservation of residues involved in binding the allosteric activator UDP-GlcNAc, the enzyme is not strictly regulated by the substrate. Unlike S. aureus MnaA, the activity of P. alvei MnaA remains unaffected by tunicamycin.

Analysis of implicit and explicit uncertainties in QSAR prediction of chemical toxicity: a case study of neurotoxicity.

Although uncertainties expressed in texts within QSAR studies can guide quantitative uncertainty estimations, they are often overlooked during uncertainty analysis. Using neurotoxicity as an example, this study developed a method to support analysis of implicitly and explicitly expressed uncertainties in QSAR modeling studies. Text content analysis was employed to identify implicit and explicit uncertainty indicators, whereafter uncertainties within the indicator-containing sentences were identified and systematically categorized according to 20 uncertainty sources. Our results show that implicit uncertainty was more frequent within most uncertainty sources (13/20), while explicit uncertainty was more frequent in only three sources, indicating that uncertainty is predominantly expressed implicitly in the field. The most highly cited sources included Mechanistic plausibility, Model relevance and Model performance, suggesting they constitute sources of most concern. The fact that other sources like Data balance were not mentioned, although it is recognized in the broader QSAR literature as an area of concern, demonstrates that the output from the type of analysis conducted here must be interpreted in the context of the broader QSAR literature before conclusions are drawn. Overall, the method established here can be applied in other QSAR modeling contexts and ultimately guide efforts targeted towards addressing the identified uncertainty sources.

Investigation of acetyl-CoA carboxylase-inhibiting herbicides that exhibit soybean crop selectivity.

The sustainable control of weed populations, particularly resistant species, is a significant challenge in agriculture around the world. The α-aryl-keto-enol (aryl-KTE) class of acetyl-CoA carboxylase (ACCase)-inhibiting herbicides represent a possible solution for the control of resistant grasses even though achieving crop selectivity remains a challenge. Herein, we present some of our investigations into identifying the most promising structural features within the aryl-KTE class that give the highest chance of achieving soybean crop selectivity, whilst also maintaining strong and broad efficacy against problematic weed species. We further examined our results by preparing new aryl-KTE molecules which were evaluated in glasshouse screening assays for their herbicidal efficacy as well as their soybean selectivity. We consider that uniting this approach with other optimization criteria, such as toxicological and environmental safety profiles, will enable the streamlining of crop protection optimizations programmes, ultimately delivering safer and more sustainable solutions to farmers and consumers. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The general glycan profiling of Dendrobium officinale and their protective effects on MIN6 cells via ERK signaling pathway.

Based on structural elucidation of natural and hydrolyzed glycans, the general glycans profiling of D. officinale were unequivocally established for the first time as follows: The results indicated that the structure of D. officinale glycans with low degree of polymerization (DP ≤ 22) was linear α-D-1,4-glucan, whereas the structure of glycans with high degree of polymerization (DP > 24) was linear acetylated 1,4-glucomannan. The content of acetyl groups and mannose to glucose (M/G) ratio increased with the degree of polymerization of D. officinale glycans. In addition, this study showed that natural D. officinale glycans protected pancreatic ß-cell damage induced by glucotoxicity through the extracellular signal-regulated kinase (ERK)1/2 pathway.

Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors.

A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC50 value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo, establishing it as a promising lead compound for further anticancer drug development.

Neisseria gonorrhoeae carbonic anhydrase inhibition.

Carbonic anhydrases (CAs) are ubiquitous enzymes that are found in all kingdoms of life. Though different classes of CAs vary in their roles and structures, their primary function is to catalyze the reaction between carbon dioxide and water to produce bicarbonate and a proton. Neisseria gonorrhoeae encodes for three distinct CAs (NgCAs) from three different families: an α-, a ß-, and a γ-isoform. This chapter details the differences between the three NgCAs, summarizing their subcellular locations, roles, essentiality, structures, and enzyme kinetics. These bacterial enzymes have the potential to be drug targets; thus, previous studies have investigated the inhibition of NgCAs-primarily the α-isoform. Therefore, the classes of inhibitors that have been shown to bind to the NgCAs will be discussed as well. These classes include traditional CA inhibitors, such as sulfonamides, phenols, and coumarins, as well as non-traditional inhibitors including anions and thiocarbamates.

QSAR Studies on a Class of Benzofuranene Cyanide Derivatives as Potential Inhibitors Targeting Staphylococcus aureus Sortase A.

BACKGROUND: Staphylococcus aureus is a widely distributed and highly pathogenic zoonotic bacterium. Sortase A represents a crucial target for the research and development of novel antibacterial drugs. OBJECTIVE: This study aims to establish quantitative structure-activity relationship models based on the chemical structures of a class of benzofuranene cyanide derivatives. The models will be used to screen new antibacterial agents and predict the properties of these molecules. METHOD: The compounds were randomly divided into a training set and a test set. A large number of descriptors were calculated using the software, and then the appropriate descriptors were selected to build the models through the heuristic method and the gene expression programming algorithm. RESULTS: In the heuristic method, the determination coefficient, determination coefficient of cross-validation, F-test, and mean squared error values were 0.530, 0.395, 9.006, and 0.047, respectively. In the gene expression programming algorithm, the determination coefficient and the mean squared error values in the training set were 0.937 and 0.008, respectively, while in the test set, they were 0.849 and 0.035. The results showed that the minimum bond order of a C atom and the relative number of benzene rings had a significant positive contribution to the activity of compounds. CONCLUSION: In this study, two quantitative structure-activity relationship models were successfully established to predict the inhibitory activity of a series of compounds targeting Staphylococcus aureus Sortase A, providing insights for further development of novel anti-Staphylococcus aureus drugs.

Shopping around: Comparing Cd(II) sorption performance of disparate functional groups-modified microcrystalline cellulose composites.

The structure-function relationship of functionalized microcrystalline cellulose (MCC) composites as adsorbents remains unclear. Herein, the orange peel-derived MCC (i.e., OP-OH-H-25) was treated by different functional agents to prepare adsorbents for cadmium (Cd(II)) removal. Mercaptoacetic acid and orthophosphoric acid did not apparently impact MCC's surface site types and contents. Alternatively, they efficiently purified OP-OH-H-25 and generated OP-OH-SH and OP-OH-P samples with increased cellulose amounts. In contrast, the glycine modification produced OP-OH-NH2 with fewer sulfhydryl/carboxyl functional groups and more amide/amino sites. The pH-dependent Cd(II) removal trends by the MCC-related materials showed three successive stages with disparate sorption modes. The Cd(II) sorption kinetics processes on OP-OH-SH, OP-OH-P, and OP-OH-NH2 reached equilibrium after 0.25 h, faster than 0.5 h on OP-OH-H-25. The maximum Cd(II) sorption capacities of MCC-related adsorbents were OP-OH-P (151.81 mg/g) > OP-OH-SH (150.80 mg/g) > OP-OH-H-25 (124.90 mg/g) > > OP-OH-NH2 (55.23 mg/g). OP-OH-P exhibited the strongest Cd(II) sorption ability under the interference of mixed aquatic components. The intrinsic Cd(II) sorption mechanisms were identified as inner-sphere complexation and cation-π bond interaction. Overall, the select priority of modifying agents is orthophosphoric acid > mercaptoacetic acid > > glycine when preparing functionalized MCC adsorbents for purifying Cd(II)-polluted water systems.

Anti-enterovirus 71 activity of native fucosylated chondroitin sulfates and their derivatives.

Enterovirus 71 (EV71) is recognized as a major causative agent of hand, foot, and mouth disease (HFMD), posing a significant global public health concern due to its widespread impact and resulting in a major public health issue worldwide. Despite its prevalence, current clinical therapy lacks effective antiviral agents. Fucosylated chondroitin sulfates (FCS) derived from sea cucumber exhibits a range of biological activities including potent antiviral effects. This study provides compelling evidence of the potent antiviral efficacy of FCS against EV71. To further elucidate the impact of structural variations on the anti-EV71 activity, native FCSs with diverse sulfation patterns and a varity of FCS derivatives were prepared and analyzed. Notably, this study presents the detailed structural characterization of FCSs from the sea cucumbers Holothuria scabra Jaege and Holothuria fuscopunctata. Analysis of the structure-activity relationships revealed that molecular weight, sulfated fucose branches, and sulfation pattern were all crucial factors contributing to the potent inhibitory effects of FCS against EV71. Interestingly, molecular weight emerged as the most significant structural determinant of the antiviral potency. These findings suggest the promising potential of utilizing FCS as an innovative EV71 entry inhibitor for the treatment of HFMD.

Identification and molecular mechanism of novel antioxidant peptide from fish sauce: A combined quantum chemistry and molecular simulation.

Fish sauce, derived from fermented fish, exhibits a notable antioxidant effect after a six-month fermentation process, and we propose that potential antioxidant peptides were present in the fish sauce. We isolated, purified, and identified potential bioactive antioxidant peptides by using fish sauce fermented for 6 months. Additionally, molecular simulation was employed to investigate the antioxidant action mechanism of these bioactive peptides. The molecular docking results revealed that FS4-1 (MHQLSKK), FS4-2 (VLDNSPER), FS4-3 (MNPPAASIK), FS6-1(VLKQAAAGR), and FS6-2 (SPDVSPRR), could dock with the Keap1 receptor. The primary force (Van der Waals' force and hydrogen bonds) and key sites (GLY509 and ALA510) of Keap1 binding to peptides were determined. The active center was located in the side chain of amino acid Met at positions C7H78 and C7H79. We here identified antioxidant peptides in fish sauce and revealed the antioxidant mechanism through molecular simulations.