Evaluation of the antimicrobial-cytotoxic activities and molecular docking study of L-cysteine ethyl ester and L-cysteine methyl ester

Chemistry perspectives of reversible covalent drugs

The rational design of targeted covalent inhibitors (TCIs) has emerged as a powerful strategy in drug discovery, known for its ability to achieve strong binding affinity and prolonged target engagement. However, the development of covalent drugs is often challenged by the need to optimize both covalent warhead and non-covalent interactions, alongside the limitations of existing compound libraries. To address these challenges, we present CovalentInDB 2.0, an updated online database designed to support covalent drug discovery. This updated version includes 8303 inhibitors and 368 targets, supplemented by 3445 newly added cocrystal structures, providing detailed analyses of non-covalent interactions. Furthermore, we have employed an AI-based model to profile the ligandability of 144 864 cysteines across the human proteome. CovalentInDB 2.0 also features the largest covalent virtual screening library with 2 030 192 commercially available compounds and a natural product library with 105 901 molecules, crucial for covalent drug screening and discovery. To enhance the utility of these compounds, we performed structural similarity analysis and drug-likeness predictions. Additionally, a new user data upload feature enables efficient data contribution and continuous updates. CovalentInDB 2.0 is freely accessible at http://cadd.zju.edu.cn/cidb/.

Covalent drugs can offer significant advantages over non-covalent drugs in terms of pharmacodynamics (i.e., target-binding properties). However, the development of covalent drugs is sometimes hampered by pharmacokinetic limitations (e.g., low bioavailability, rapid metabolism and toxicity due to off-target binding). Polymeric nanoparticles offer a potential solution to these limitations. Delivering covalent drugs via polymeric nanoparticles provides myriad benefits in terms of drug solubility, permeability, lifetime, selectivity, controlled release and the opportunity for synergistic administration alongside other drugs. In this short review, we examine each of these benefits in turn, illustrated through multiple case studies.

Resistance to folate antagonists is caused by mutations in the dihydrofolate reductase (DHFR) genes. These mutations affect the amino acids at positions 51, 59, 108 and 164 of DHFR, which appear to play a major role in malaria treatment failure. Therefore, the design of new drugs able to overcome the problem of antifolate drug resistance should receive urgent attention. In this study, a three-dimensional quantitative structure-activity relationship (3 D-QSAR) and molecular docking studies have been performed on antimalarial quinazoline derivatives. The CoMFA (Q2 = 0.63, R2 = 0.83 and = 0.70) and the CoMSIA (Q2 = 0.584, R2 = 0.816, and = 0.73) models show a good prediction of antimalarial activity. The reliability and robustness of the proposed models have been tested using several validation methods, which showed that the steric, electrostatic, hydrophobic and H-bond acceptor fields of the CoMSIA model play a key role in the prediction of antimalarial activity. Molecular docking studies reveal important interactions between two isomeric compounds (meta and para) and the DHFR receptor in its wild and mutant forms. The obtained outcomes of molecular docking studies have been validated using a new method based on visual inspection. The DFT study of the two isomeric compounds confirms clearly the trends of 3 D-QSAR and molecular docking for the design of new compounds. Moreover, the consistency between theoretical, 3 D-QSAR and molecular docking analysis provides guidance for the design of new drug candidates, which have been tested using ADMET properties and drug likeness analysis. Communicated by Ramaswamy H. Sarma

Crystal structure, Hirshfeld analysis and computational study on tin (IV) complex: Insights from synthesis, spectroscopic, anticancer activity and molecular docking studies

Biocompatible and bioorthogonal conjugation reactions have proven to be powerful tools in biological research and medicine. While the advent of bioorthogonal conjugation chemistries greatly expands our capacity to interrogate specific biomolecules in situ, biocompatible reactions that target endogenous reactive groups have given rise to a number of covalent drugs as well as a battery of powerful research tools. Despite the impressive progress, limitations do exist with the current conjugation chemistries. For example, most known bioorthogonal conjugations suffer from slow reaction rates and imperfect bioorthogonality. On the other hand, covalent drugs often display high toxicity due to off-target labeling and immunogenicity. These limitations demand continued pursuit of conjugation chemistries with optimal characteristics for biological applications. A spate of papers appearing in recent literature report the conjugation chemistries of 2-formyl and 2-acetyl phenylboronic acids (abbreviated as 2-FPBA and 2-APBA, respectively). These simple reactants are found to undergo fast conjugation with various nucleophiles under physiological conditions, showing great promise for biological applications. The versatile reactivity of 2-FPBA and 2-APBA manifests in dynamic conjugation with endogenous nucleophiles as well as conjugation with designer nucleophiles in a bioorthogonal manner. 2-FPBA/APBA conjugates with amines in biomolecules, such as lysine side chains and aminophospholipids, in a highly dynamic manner to give iminoboronates. In contrast to typical imines, iminoboronates enjoy much improved thermodynamic stability, yet are kinetically labile for hydrolysis due to imine activation bythe boronic acid. Dynamic conjugations as such presenta novel binding mechanism analogous to hydrogen bonding and electrostatic interactions. Implementation of this covalent binding mechanism has yielded reversible covalent probes of prevalent bacterial pathogens. It has also resulted in reversible covalent inhibitors of a therapeutically important protein Mcl-1. Such covalent probes/inhibitors with 2-FPBA/APBA warheads avoid permanent modification of their biological target, potentially able to mitigate off-target labeling and immunogenicity of covalent drugs. The dynamic conjugation of 2-FPBA/APBA has been recently extended to N-terminal cysteines, which can be selectively targeted via formation of a thiazolidino boronate (TzB) complex. The dynamic TzB formation expands the toolbox for site-specific protein labeling and the development of covalent drugs. On the front of bioorthogonal conjugation, 2-FPBA/APBA has been found to conjugate with α-nucleophiles under physiologic conditions with rate constant ( k2) over 1000 M-1 s-1, which overcomes the slow kinetics problems and rekindles the interest of using the conjugation of α-nucleophiles for biological studies. With fast kinetics being a shared feature, this family of conjugation chemistries gives remarkably diverse product structures depending on the choice of nucleophile. Importantly, both dynamic and irreversible conjugations have been developed, which we believe will enable a wide array of applications in biological research. In this Account, we collectively examine this rapidly expanding family of conjugation reactions, seeking to elucidate the unifying principles that would guidefurther development of novel conjugation reactions, as well as their applications in biology.

Investigation of cytotoxic activity properties of etoxazole towards human cancer and healthy cell lines and molecular docking studies.

To prevent the deterioration of the global environment, the reduction of chemical pesticide use and the development of eco-friendly pest control technologies are urgent issues. Our recent study revealed that the production of reactive oxygen species (ROS) by dual oxidase (Duox) plays a pivotal role in stabilizing the tracheal network by intermediating the tyrosine cross-linking of proteins that constitute trachea. Notably, the formation of dityrosine bonds by ROS can be inhibited by the intake of an antioxidant cysteine derivative N-acetyl-L-cysteine (NAC), which can suppress insect respiration. In this study, we screened for the derivatives showing insecticidal activity and tracheal formation inhibition. As a result of investigating the soybean pest bug Riptortus pedestris, cysteine and methionine derivatives showed respiratory formation inhibition and high insecticidal activity. In particular, NAC had a slow-acting insecticidal effect, while L-cysteine methyl ester (L-CME) showed relatively fast-acting insecticidal activity. Furthermore, the insecticidal activity of these derivatives was also detected in Drosophila, mealworms, cockroaches, termites, and plant bugs. Our results suggest that some antioxidant compounds have specific tracheal inhibitory activity in different insect species and they may be used as novel pest control agents upon further characterization.

Recent advances in targeted covalent inhibitors have aroused significant interest for their potential in drug development for difficult therapeutic targets. Proteome-wide profiling of functional residues is an integral step of covalent drug discovery aimed at defining actionable sites and evaluating compound selectivity in cells. A classical workflow for this purpose is called IsoTOP-ABPP, which employs an activity-based probe and two isotopically labeled azide-TEV-biotin tags to mark, enrich, and quantify proteome from two samples. Here we report a novel isobaric 11plex-AzidoTMT reagent and a new workflow, named AT-MAPP, that significantly expands multiplexing power as compared to the original isoTOP-ABPP. We demonstrate its application in identifying cysteine on- and off-targets using a KRAS G12C covalent inhibitor ARS-1620. However, changes in some of these hits can be explained by modulation at the protein and post-translational levels. Thus, it would be crucial to interrogate site-level bona fide changes in concurrence to proteome-level changes for corroboration. In addition, we perform a multiplexed covalent fragment screening using four acrylamide-based compounds as a proof-of-concept. This study identifies a diverse set of liganded cysteine residues in a compound-dependent manner with an average hit rate of 0.07% in intact cell. Lastly, we screened 20 sulfonyl fluoride-based compounds to demonstrate that the AT-MAPP assay is flexible for noncysteine functional residues such as tyrosine and lysine. Overall, we envision that 11plex-AzidoTMT will be a useful addition to the current toolbox for activity-based protein profiling and covalent drug development.

In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.

Covalent inhibitors have emerged as an important drug class in recent years, largely due to their many unique advantages as compared to noncovalent inhibitors, including longer duration of action, lower prolonged systemic exposure, higher potency, and selectivity. However, the potential off-target toxicity of covalent inhibitors, particularly of irreversible covalent inhibitors, represents a great challenge in covalent drug development. Therefore, accurate calculation of protein covalent inhibitor reaction kinetics to guide the design of selective inhibitors would greatly benefit covalent drug discovery efforts. In the present paper, we present a computational method to calculate the relative reaction kinetics between congeneric irreversible covalent inhibitors and their protein receptors. The method combines density functional theory calculations of the transition state barrier height of the rate-limiting step for reaction between the warhead of the inhibitor and a single protein residue, and molecular-mechanics-based free energy calculations to account for the interactions between the ligand in the transition state and the protein environment. The method was tested on four pharmaceutically interesting irreversible covalent binding systems involving 28 ligands; the mean unsigned error (MUE) of the relative reaction rate for all pairs of ligands between the predictions and experimental results for these tested systems is 0.79 log unit. This is to our knowledge the first time where the reaction kinetics of protein irreversible covalent inhibition have been directly calculated with physics-based free energy calculation methods and transition state theory. We anticipate the outstanding accuracy demonstrated here across a broad range of target classes will have a strong impact on the design of selective covalent inhibitors.

Secondary metabolites isolated from Cryptocarya was known to have various activity especially their cytotoxicity in P388 cell. There were two species of Cryptocarya studied in this research that were Cryptocarya konishii and Cryptocarya lucida. In both species, 8 isolate compounds had bioactivity as anticancer in P388 cells. This study aimed to know the binding affinity and ADMET properties of each isolated compound through P-glycoprotein substrate since this protein was reported to be responsible for the inhibition of P388 cells. Molecular docking was performed using AutoDock4 and AutoDockTools software to know the binding energy and interaction of isolate compounds against the P-glycoprotein substrate. ADMET properties calculation was done using the pkCSM web server for all compounds. Molecular docking results showed that Kurzichalcolactone B (7) isolated from C. lucida had the lowest binding energy. It resulted in the highest total intermolecular energy from the contribution of van der Waals and hydrogen bond energy. The lowest binding energy is indicating the stable interaction of ligand and substrate. Calculation of ADMET properties resulted that some of the isolate compounds fulfilling the minimum standard parameters in ADMET properties.

Non-covalent interaction, biological activity prediction, topology and molecular docking studies on adenine derivative

Piperazinium bis (4-hydroxybenzenesulphonate) (P4HBS) was studied using FT-IR, FT-Raman, UV spectra, and quantum chemical calculations. To obtain the geometry of the molecule, computational methods were used with the Gaussian’09w package and B3LYP/cc-pVTZ as the basis set. The stretching wave number of hydrogen bond donor NH2 + and hydrogen bond acceptor SO3 − is red shifted due to protonation, according to vibrational analysis. Frontier molecular orbital analysis was used to confirm the molecule’s molecular reactivity and kinetic stability. The electronic transition observed in the UV-visible spectrum, which was measured experimentally, was identified using TD-DFT. MEP plot, Fukui function. Natural population analysis confirm that OH groups and SO3 groups are electrophilic attack sites, while hydrogen atoms in the Piperazinium ring are nucleophilic attack sites. The Independent Gradient Model (IGM) and Hirshfeld surface analysis were used to determine the weak van der Waals and strong intermolecular hydrogen bonding interactions, respectively. The antifungal activity against the fungus Candida albicans and Aspergillus flaves was determined by the disk diffusion technique. Through binding energy, molecular docking studies were performed to identify the effective lead compound against the C. albicans fungal pathogen. ADMET properties with improved pharmacokinetic properties were predicted.

Efficacy of decontamination foam on a non-polar hazardous chemical surrogate