Potential Ligand Binding Research Articles

In silico assessment of biocompatibility and toxicity: molecular docking and dynamics simulation of PMMA-based dental materials for interim prosthetic restorations

Aim: This study aimed to comprehensively assess the biocompatibility and toxicity profiles of poly(methyl methacrylate) (PMMA) and its monomeric unit, methyl methacrylate (MMA), crucial components in dental materials for interim prosthetic restorations. Methodology: Molecular docking was employed to predict the binding affinities, energetics, and steric features of MMA and PMMA with selected receptors involved in bone metabolism and tissue development, including RANKL, Fibronectin, BMP9, NOTCH2, and other related receptors. The HADDOCK standalone version was utilized for docking calculations, employing a Lamarckian genetic algorithm to explore the conformational space of ligand-receptor interactions. Furthermore, molecular dynamics (MD) simulations over 100 nanoseconds were conducted using the GROMACS package to evaluate dynamic actions and structural stability. The LigandScout was utilized for pharmacophore modeling, which employs a shape-based screening approach to identify potential ligand binding sites on protein targets. Results: The molecular docking studies elucidated promising interactions between PMMA and MMA with key biomolecular targets relevant to dental applications. MD simulation results provided strong evidence supporting the structural stability of PMMA complexes over time. Pharmacophore modeling highlighted the significance of carbonyl and hydroxyl groups as pharmacophoric features, indicating compounds with favorable biocompatibility profiles. Conclusion: This study underscores the potential of PMMA in dental applications, emphasizing its structural stability, molecular interactions, and safety considerations. These findings lay a foundation for future advancements in dental biomaterials, guiding the design and optimization of materials for enhanced biocompatibility. Future directions include experimental validation of computational findings and the development of PMMA-based dental materials with improved biocompatibility and clinical performance.Graphical

Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms.

Transient receptor potential (TRP) channels are a large and diverse family of transmembrane ion channels that are widely expressed, have important physiological roles, and are associated with many human diseases. These proteins are actively pursued as promising drug targets, benefitting greatly from advances in structural and mechanistic studies of TRP channels. At the same time, the complex, polymodal activation and regulation of TRP channels have presented formidable challenges. In this short review, we summarize recent progresses toward understanding the structural basis of TRP channel function, as well as potential ligand binding sites that could be targeted for therapeutics. A particular focus is on the current understanding of the molecular mechanisms of TRP channel activation and regulation, where many fundamental questions remain unanswered. We believe that a deeper understanding of the functional mechanisms of TRP channels will be critical and likely transformative toward developing successful therapeutic strategies targeting these exciting proteins. This endeavor will require concerted efforts from computation, structural biology, medicinal chemistry, electrophysiology, pharmacology, drug safety and clinical studies.

In Vitro and In Silico Studies on 4-Nitroacetophenone Thiosemicarbazone Potential Cytotoxicity Against A549 Cell Lines.

Lung malignancy is a major worldwide issue that occurs due to the dysregulation of various growth factors. Lung cancer has no apparent signs in the early stages, which makes it harder to catch it in time and leads to a higher fatality rate. So, the goal of this work was to create and analyze a novel chemical molecule called 4-nitro acetophenone thiosemicarbazone (4-NAPTSc) against the lung cancer cell line A549 and human non-tumorigenic lung epithelial cell line BAES-2B. The ligand was synthesized by refluxing the reaction mixture of 4-nitro acetophenone and thiosemicarbazide and was further characterized by UV, FTIR, and 1H and 13C NMR and Differential Scanning Calorimetry (DSC) study. Cytotoxicity assay/MTT (3-(4,5-dimethylthiazol-2-yl))2,5-diphenyltetrazolium bromide) was used to evaluate the cytotoxicity of the compound. Epidermal growth factor receptors (EGFR), polo-like kinase-1 (PLK1), and vascular endothelial growth factor receptors (VEGFR) were chosen as the target proteins for molecular docking to find potential ligand binding sites and inhibit their function. A novel yellow-colored crystalline solid has been synthesized. 4-NAPTSc had an IC50 of 2.93 μg/mL against the A549 lung cancer cells. When the dosage is increased from 5 to 15 μg/mL along with time, the cell viability falls. Docking results showed that the compound binds with the targeted proteins' amino acid residues, and the likeness profile of the compound is also favorable. This study reveals that the compound has the potential for further investigation and can be used in multitargeted cancer therapies.

The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites.

Glycine Transporter 2 (GlyT2) inhibitors have shown considerable potential as analgesics for the treatment of neuropathic pain but also display considerable side effects. One potential source of side effects is irreversible inhibition. In this study, we have characterized the mechanism of ORG25543 inhibition of GlyT2 by first considering three potential ligand binding sites on GlyT2-the substrate site, the vestibule allosteric site and the lipid allosteric site. The three sites were tested using a combination of molecular dynamics simulations and analysis of the inhibition of glycine transport of a series point mutated GlyT2 using electrophysiological methods. We demonstrate that the lipid allosteric site on GlyT2 is the most likely binding site for ORG25543. We also demonstrate that cholesterol derived from the cell membrane can form specific interactions with inhibitor-bound transporters to form an allosteric network of regulatory sites. These observations will guide the future design of GlyT2 inhibitors with the objective of minimising on-target side effects and improving the therapeutic window for the treatment of patients suffering from neuropathic pain.

Molecular docking and molecular dynamics simulation studies on the effect of baicalein on breast and ovarian cancers

Purpose: To carry out molecular docking and molecular dynamics simulation analysis on the effect of baicalein and its derivatives on breast cancer and ovarian cancer.Methods: The potential ligand binding site of cyclooxygenase-2 (COX-2) was predicted, and virtual screening was carried out on baicalein, a plant-based herbal compound, and its natural derivatives. Furthermore, molecular dynamics (MD) simulation was used to confirm the validity and stability of the docking protocol.Results: Molecular docking showed strong molecular interaction of baicalein and its derivatives with COX-2. The results of docking showed that baicalein, baicalein 6-O-glucoside, and baicalein monohydrate had total scores of -528.26, -505.65 and -496.83 kj/mol, respectively, relative to scores of -481.29 kj/mol for ibuprofen (NSAID), and -466.80 kj/mol for the anticancer agent, olaparib (p < 0.05). There were strong hydrogen bonding and electrostatic interactions at the active of the enzyme when compared to market-approved drugs such as COX-2 inhibitors (NSAIDs) and other anti-cancer drugs. Baicalein and its derivatives, as plant-based compounds, had lower probabilities of health effects such as heart attacks and strokes, than synthetic drugs.Conclusion: Baicalein and its derivatives have promising potential as effective anti-breast cancer and anti-ovarian cancer agents through inhibition of COX-2 but these findings require validation via in vivo studies

Crystal structure of domain of unknown function 507 (DUF507) reveals a new protein fold

The crystal structure of the domain of unknown function family 507 protein from Aquifex aeolicus is reported (AaDUF507, UniProt O67633, 183 residues). The structure was determined in two space groups (C2221 and P3221) at 1.9 Å resolution. The phase problem was solved by molecular replacement using an AlphaFold model as the search model. AaDUF507 is a Y-shaped α-helical protein consisting of an anti-parallel 4-helix bundle base and two helical arms that extend 30-Å from the base. The two crystal structures differ by a 25° rigid body rotation of the C-terminal arm. The tertiary structure exhibits pseudo-twofold symmetry. The structural symmetry mirrors internal sequence similarity: residues 11–57 and 102–148 are 30% identical and 53% similar with an E-value of 0.002. In one of the structures, electron density for an unknown ligand, consistent with nicotinamide or similar molecule, may indicate a functional site. Docking calculations suggest potential ligand binding hot spots in the region between the helical arms. Structure-based query of the Protein Data Bank revealed no other protein with a similar tertiary structure, leading us to propose that AaDUF507 represents a new protein fold.

Modification of the structural stability of human serum albumin in rheumatoid arthritis.

Differential scanning calorimetry (DSC) can indicate changes in structure and/or concentration of the most abundant proteins in a biological sample via heat denaturation curves (HDCs). In blood serum for example, HDC changes result from either concentration changes or altered thermal stabilities for 7-10 proteins and has previously been shown capable of differentiating between sick and healthy human subjects. Here, we compare HDCs and proteomic profiles of 50 patients experiencing joint-inflammatory symptoms, 27 of which were clinically diagnosed with rheumatoid arthritis (RA). The HDC of all 50 subjects appeared significantly different from expected healthy curves, but comparison of additional differences between the RA and the non-RA subjects allowed more specific understanding of RA samples. We used mass spectrometry (MS) to investigate the reasons behind the additional HDC changes observed in RA patients. The HDC differences do not appear to be directly related to differences in the concentrations of abundant serum proteins. Rather, the differences can be attributed to modified thermal stability of some fraction of the human serum albumin (HSA) proteins in the sample. By quantifying differences in the frequency of artificially induced post translational modifications (PTMs), we found that HSA in RA subjects had a much lower surface accessibility, indicating potential ligand or protein binding partners in certain regions that could explain the shift in HSA melting temperature in the RA HDCs. Several low abundance proteins were found to have significant changes in concentration in RA subjects and could be involved in or related to binding of HSA. Certain amino acid sites clusters were found to be less accessible in RA subjects, suggesting changes in HSA structure that may be related to changes in protein-protein interactions. These results all support a change in behavior of HSA which may give insight into mechanisms of RA pathology.

Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein

Ligand-binding promiscuity in detoxification systems protects the body from toxicological harm but is a roadblock to drug development due to the difficulty in optimizing small molecules to both retain target potency and avoid metabolic events. Immense effort is invested in evaluating metabolism of molecules to develop safer, more effective treatments, but engineering specificity into or out of promiscuous proteins and their ligands is a challenging task. To better understand the promiscuous nature of detoxification networks, we have used X-ray crystallography to characterize a structural feature of pregnane X receptor (PXR), a nuclear receptor that is activated by diverse molecules (with different structures and sizes) to up-regulate transcription of drug metabolism genes. Wefound that large ligands expand PXR's ligand-binding pocket, and the ligand-induced expansion occurs through a specific unfavorable compound-protein clash that likely contributes to reduced binding affinity. Removing the clash by compound modification resulted in more favorable binding modes with significantly enhanced binding affinity. We then engineered the unfavorable ligand-protein clash into a potent, small PXR ligand, resulting in marked reduction in PXR binding and activation. Structural analysis showed that PXR is remodeled, and the modified ligands reposition in the binding pocket to avoid clashes, but the conformational changes result in less favorable binding modes. Thus, ligand-induced binding pocket expansion increases ligand-binding potential of PXR but is an unfavorable event; therefore, drug candidates can be engineered to expand PXR's ligand-binding pocket and reduce their safety liability due to PXR binding.

Label-free biosensing of lignans for therapeutics using engineered model surfaces

The label-free interaction analysis of macromolecules and small molecules has increasing importance nowadays, both in diagnostics and therapeutics. In the blood vascular system, human serum albumin (HSA) is a vital globular transport protein with potential multiple ligand binding sites. Characterizing the binding affinity of compounds to HSA is essential in pharmaceutics and in developing new compounds for clinical application. Aryltetralin lignans from the roots of Anthriscus sylvestris are potential antitumor therapeutic candidates, but their molecular scale interactions with specific biomolecules are unrevealed. Here, we applied the label-free grating-coupled interferometry (GCI) biosensing method with a polycarboxylate-based hydrogel layer with immobilized HSA on top of it. With this engineered model surface, we could determine the binding parameters of two novel aryltetralin lignans, deoxypodophyllotoxin (DPT), and angeloyl podophyllotoxin (APT) to HSA. Exploiting the multi-channel referencing ability, the unique surface sensitivity, and the throughput of GCI, we first revealed the specific biomolecular interactions. Traditional label-free kinetic measurements were also compared with a novel, fast way of measuring affinity kinetics using less sample material (repeated analyte pulses of increasing duration (RAPID)). Experiments with well-characterized molecular interactions (furosemide to carbonic-anhydrase (CAII) and warfarin, norfloxacin to HSA) were performed to prove the reliability of the RAPID method. In all investigated cases, the RAPID and traditional measurement gave similar affinity values. In the case of DPT, the measurements and relevant modeling suggested two binding sites on HSA, with dissociation constant values of Kd1 = 1.8 ± 0.01 μM, Kd2 = 3 ± 0.02 μM. In the case of APT, the experiments resulted in Kd1 = 9 ± 1.7 μM, Kd2 = 28 ± 0.3 μM. The obtained binding values might suggest the potential medical application of DPT and APT without further optimization of their binding affinity to HSA. These results could be also adapted to other biomolecules and applications where sample consumption and the rapidity of the measurements are critical.

Computational prediction and in vitro analysis of the potential ligand binding site within the extracellular ATP receptor, P2K2

ABSTRACT The plant extracellular ATP (eATP) receptor, P2K2, binds eATP with strong ligand affinity through its extracellular lectin domain. Ligand binding activates the intracellular kinase domain of P2K2 resulting in a variety of intracellular responses and, ultimately, increased plant immunity to invading fungal and bacterial pathogens. Here, using a computational prediction approach, we developed a tertiary structure model of the P2K2 extracellular lectin domain. In silico target docking of ATP to the P2K2-binding site predicted interaction with several residues through hydrophobic interactions and hydrogen bonding. Our confirmation of the modeling was obtained by showing that H99, R144, and S256 are key residues essential for in vitro binding of ATP by P2K2.

Molecular dynamics study of MEIG1 interactions with PACRG.

Interactions between the meiosis expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) protein are critical in the formation of mature sperm cells. Targeting either MEIG1 or PACRG protein could be a contraceptive strategy. The W50A and Y68A mutations on MEIG1 are known to interrupt the MEIG1-PACRG interactions resulting in defective sperm cells. However, the details about how the mutants disrupt the protein-protein binding are not clear. In this study, we reveal insights on MEIG1 and PACRG protein dynamics by applying Gaussian accelerated molecular dynamics (GaMD) simulations and post-GaMD analysis. Our results show that the mutations destabilize the protein-protein interfacial interaction. The effect of the Y68A mutation is more significant than W50A as Y68 forms stronger polar interactions with PACRG. Because both human and mouse models demonstrate similar dynamic properties, the findings from mouse proteins can be applied to the human system. Moreover, we report a potential ligand binding pocket on the MEIG1 and PACRG interaction surface that could be a target for future drug design to inhibit the MEIG1-PACRG interaction. Our work provides a fundamental understanding of MEIG1 and PACRG protein dynamics, paving the way for drug discovery in male-based contraception.

Withania somnifera: The Wonder Plant with Withanolide E and J Inhibit Inflammatory Mediator AP-1 Factor

Background: Inflammation is a natural biological response of the body tissues to harmful stimuli, such as damaged cells, irritants or pathogens and it is a protective response involving blood vessels, immune cells and molecular mediators. Activator Protein-1 (AP-1) is a dimer composed of both homo and hetero dimers with jun and fos sub families. The heterodimer cfos-cjun complex is up regulated in several inflammatory diseases such as asthma, rheumatoid arthritis, psoriasis etc. Since ancient time, several plants were used as anti-inflammatory sources. Withania somnifera is a vital plant having well documented anti-inflammatory properties. In this study, the phytochemicals of Withania somnifera are used to study the inhibitory effect on inflammatory mediator AP-1 factor. Objective: Determination of inhibitory effect of Withania somnifera phytochemicals against AP-1 factor (cfos-cjun complex). Method: In the present study, phytochemicals of Withania somnifera were retrieved from IMPPAT database and all the retrieved molecules were employed for screening of in-silico pharmacological properties using in-silico tools such as SwissADME and ProTox II. Further, Molecular interactions of receptor and the ligands were carried out by Autodock 4.1 tool. Results: Total 90 phytochemicals of Withania somnifera were subjected for IMPPAT database. Among those 21 Phytochemicals shown the appropriate drug similarity characteristics. Autodock 4.1 tool used to analyse the binding effectiveness of these 21 phytochemicals. The excellent inhibitory action in comparison to others was shown by Withanolide E and Withanolide J molecules. Interactions pattern showed that SER and ARG amino acids participate in the formation of drug hydrogen bonds. Conclusion: Among the 90 phytochemicals of Withania somnifera, only two molecules showed potential ligand binding ability. Further, in-vitro studies may validate the findings.

Overcoming hysteresis in ligand binding potential of mean force calculations.

Accurate estimation of ligand binding free energy and elucidation of the corresponded binding pathway are key challenges in computational drug design. Umbrella sampling (US) molecular dynamic simulations are widely used to tackle these challenges; however, they frequently suffer from massive hysteresis between the ligand binding and unbinding pathways, limiting the applicability of US for ligand-protein interaction studies. The convergence of US is affected by the complexity of the system, the selection of reaction coordinate(s), simulation time, and by the selection of additional restraints.

Molecular dynamics study reveals key disruptors of MEIG1-PACRG interaction.

Interactions between the meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) protein are critical in the formation of mature sperm cells. Targeting either MEIG1 or PACRG protein could be a contraceptive strategy. The W50A and Y68A mutations on MEIG1 are known to interrupt the MEIG1-PACRG interactions resulting in defective sperm cells. However, the details about how the mutants disrupt the protein-protein binding are not clear. In this study, we reveal insights on MEIG1 and PACRG protein dynamics by applying Gaussian-accelerated molecular dynamics (GaMD) simulations and post-GaMD analysis. Our results show that the mutations destabilize the protein-protein interfacial interaction. The effect of the Y68A mutation is more significant than W50A as Y68 forms stronger polar interactions with PACRG. Because both human and mouse models demonstrate similar dynamic properties, the findings from mouse proteins can be applied to the human system. Moreover, we report a potential ligand binding pocket on the MEIG1 and PACRG interaction surface that could be a target for future drug design to inhibit the MEIG1-PACRG interaction. PACRG shows more qualified pockets along the protein-protein interface, implying that it is a better target than MEIG1. Our work provides a fundamental understanding of MEIG1 and PACRG protein dynamics, paving the way for drug discovery in male-based contraception.

Exploration of Cytochrome P450 Structure and Function in In Silico Assays for Toxicity

Cytochrome P450 (CYP or P450) enzymes are known for their role in detoxifying xenobiotics and may at times cause toxicity. CYP1A1gene polymorphisms have been linked to susceptibility risks of various cancers and neoplasms, including bladder cancer. The aim of the study was to use bioinformatics tools to examine structural differences in CYP1A1 wild type and isoforms 2 and 3. Protein sequences of selected CYPs were retrieved from the NCBI protein databank and GenPept. Sequence homologies were searched for by BLAST, and by multiple sequence alignments. Protein structural characteristics such as ligand binding and secondary structure prediction were analyzed by Phyre. The CYPIA1 wild type and isoforms had 33 % variation in their amino acid residues and binding sites. The predicted binding sites for the first 6 amino acid residues were similar between the wild type and isoform two; however, the average distances from the ligands differed. The predicted secondary structure of the CYP1A1 isoform 3 exhibited the widest difference from the wild type in the percentage of disordered helix (17%), alpha helix (66%), beta strand (3%) and trans‐membrane domains (12%). Differences in nucleotide sequence between the CYP1A1 wild type and isoforms caused a change in the protein structure which further altered the trans‐membrane topology and ligand binding potential of the protein. These findings indicate structural deficits among the three Cytochrome P450 isoforms, suggesting the possible conferment of risks to toxicity and associated diseases.

Fragment screening and structural analyses highlight the ATP-assisted ligand binding for inhibitor discovery against type 1 methionyl-tRNA synthetase.

Methionyl-tRNA synthetase (MetRS) charges tRNAMet with l-methionine (L-Met) to decode the ATG codon for protein translation, making it indispensable for all cellular lives. Many gram-positive bacteria use a type 1 MetRS (MetRS1), which is considered a promising antimicrobial drug target due to its low sequence identity with human cytosolic MetRS (HcMetRS, which belongs to MetRS2). Here, we report crystal structures of a representative MetRS1 from Staphylococcus aureus (SaMetRS) in its apo and substrate-binding forms. The connecting peptide (CP) domain of SaMetRS differs from HcMetRS in structural organization and dynamic movement. We screened 1049 chemical fragments against SaMetRS preincubated with or without substrate ATP, and ten hits were identified. Four cocrystal structures revealed that the fragments bound to either the L-Met binding site or an auxiliary pocket near the tRNA CCA end binding site of SaMetRS. Interestingly, fragment binding was enhanced by ATP in most cases, suggesting a potential ATP-assisted ligand binding mechanism in MetRS1. Moreover, co-binding with ATP was also observed in our cocrystal structure of SaMetRS with a class of newly reported inhibitors that simultaneously occupied the auxiliary pocket, tRNA site and L-Met site. Our findings will inspire the development of new MetRS1 inhibitors for fighting microbial infections.

Integrated computer-aided drug design and biophysical simulation approaches to determine natural anti-bacterial compounds for Acinetobacter baumannii

Acinetobacter baumannii is a nosocomial bacterial pathogen and is responsible for a wide range of diseases including pneumonia, necrotizing fasciitis, meningitis, and sepsis. The enzyme 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase (encoded by aroA gene) in ESKAPE pathogens catalyzes the sixth step of shikimate pathway. The shikimate pathway is an attractive drug targets pathway as it is present in bacteria but absent in humans. As EPSP is essential for the A. baumannii growth and needed during the infection process, therefore it was used as a drug target herein for high-throughput screening of a comprehensive marine natural products database (CMNPD). The objective was to identify natural molecules that fit best at the substrate binding pocket of the enzyme and interact with functionally critical residues. Comparative assessment of the docking scores allowed selection of three compounds namely CMNPD31561, CMNPD28986, and CMNPD28985 as best binding molecules. The molecules established a balanced network of hydrophobic and hydrophilic interactions, and the binding pose remained in equilibrium throughout the length of molecular simulation time. Radial distribution function (RDF) analysis projected key residues from enzyme active pocket which actively engaged the inhibitors. Further validation is performed through binding free energies estimation that affirms very low delta energy of <−22 kcal/mol in MM-GBSA method and <−12 kcal/mol in MM-PBSA method. Lastly, the most important active site residues were mutated and their ligand binding potential was re-investigated. The molecules also possess good druglike properties and better pharmacokinetics. Together, these findings suggest the potential biological potency of the leads and thus can be used by experimentalists in vivo and in vitro studies.

Thalidomide-based inhibitor for TNF-\u03b1: designing and Insilico evaluation

BackgroundInflammatory diseases are the vast array of disorders caused by inflammation. During most inflammatory events, many cytokines expressions were modulated, and one such cytokine is tumor necrosis factor-alpha (TNF-α). TNF-α is mainly secreted by monocytes and macrophages. Notably, it has been proposed as a therapeutic target for several diseases. The anti-TNF biology approach is mainly based on monoclonal antibodies. The fusion protein and biosimilars are prevalent in treating inflammation for decades. Only a few small molecule inhibitors are available to inhibit the expression of TNF-α, and one such promising drug was thalidomide. Therefore, the study was carried out to design thalidomide-based small molecule inhibitors for TNF-α. The main objective of our study is to design thalidomide analogs to inhibit TNF-α using the insilico approach.ResultsSeveral thalidomide analogs were designed using chemsketch. After filtration of compounds through ‘Lipinski rule of 5’ by Molinspiration tool, as a result, five compounds were selected. All these compounds were subjected to molecular docking, and the study showed that all five compounds had good binding energy. However, based on ADMET predictions, two compounds (S3 and S5) were eliminated.ConclusionsOur preliminary results suggest that S1, S2, S4 compounds showed potential ligand binding capacity with TNF-α and, interestingly, with limited or no toxicity. Our preliminary investigation and obtained results have fashioned more interest for further in vitro studies.

Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones.

This study aims are the synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1- methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines. Many derivatives of quinoline-2-on have been interested to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinoline-pyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities. α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity. 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α,β-unsaturated ketones in the presence of piperidine as catalyst. 2- Amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method. Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin- 2'-on-3'-yl)pyrimidines with yields of 58-74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f. New substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

Synthesis and Physicochemical Studies for Novel Bioactive Metal Complexes of Macrolide Antibiotic Tylosin

Tylosin is a well-established antibiotic that has been widely employed in human and veterinary medicines. It can act as a potential ligand binding metal ions due to various donor atoms in the structure. Our study on the complexation of various metal ions with tylosin ligand revealed that they preferably coordinate with mycaminose fragment to establish Novel trends complexes. Tylosin ligand (TYS) behaves as bidentate for complexation with different metal ions such as Cr(III), Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II). Various essential metal complexes of tylosin were synthesized and characterized by techniques such as UV, IR, Elemental analysis, magnetic susceptibility and ESR spectra of Cu(II) complex. These techniques are used to know their geometries and mode of bonding, with stoichiometry, 2:2 (M:L). Thermal analysis (TGA and DTA) of ligands and their metal complexes were carried out to distinguish between the coordinate and hydrate solvents and to estimate the stability ranges, peak temperatures. The thermodynamic parameters, such as activation energy (ΔE*), the enthalpy of activation (ΔH*), entropy of activation (ΔS*) and Gibbs free energy (ΔG*) are calculated and discussed. Some tylosin complexes show higher activity than tylosin for some bacterial and fungal strains. Low concentration value of minimum inhibitory concentration (MIC) results is 15.625 μg/ml for both complexes [Zn2(TYS)2Cl2(H2O)4]·25H2O and [Cu2(TYS)2Cl2(H2O)4]·25H2O with B. cereus genus maybe a valuable data used to produce novel therapeutic agent. This study constitutes several essential aspects for future research on tylosin metal complexes as antibacterial assessment and as potential medicinal agents.