Docking Studies Research Articles

Assessing the structural and foaming property changes in egg yolk proteins due to malondialdehyde: Experimental and molecular docking studies

This study evaluated the effects of varying levels of malondialdehyde (MDA) on the structural and foaming properties of the egg yolk proteins (EYPs), and the interaction between them was explored by molecular docking. The results showed that oxidative modification due to MDA increased the carbonyl content of EYPs by 4.49 times. Simultaneously, the total sulfhydryl content was reduced by 21.47%, and the solubility of EYPs was significantly decreased (p < 0.05). Continuous oxidation disorders the previously ordered structure of EYPs. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that some proteins underwent crosslinking and aggregation with increased MDA oxidation, aligning with changes in particle size and zeta-potential. Moderate oxidation (<1 mmol/L) enhanced the foaming capacity and foam stability of EYPs. Additionally, molecular docking results uncovered favorable interactions between MDA and specific EYPs, primarily through hydrogen bonding. This research offers valuable insights into managing the functional and quality changes of yolk products during processing.

Investigation of Polyvinyl Alcohol (PVA)-Sakacin P Interaction by Molecular Docking Method

Aim: Group IIA bacteriocins, which contain unmodified amino acids and have antimicrobial activity, are a very broad group. Sakacins in this group are bacteriocins produced by Lactobacillus sakei. The most well-known sakacins are Sakacin A, G, K, P, and Q. In particular, Sakacin A and P are well characterized. This study aims to examine the interaction between a single monomer of PVA polymer and Sakacin P bacteriocin. Method: In t this study, the interaction of a single monomer of PVA polymer, which is among the water-soluble, biocompatible synthetic polymers, and Sakacin P bacteriocin, which has a protein structure, was investigated by molecular docking method. Results: As a result of our molecular docking study, the presence of binding affinity between the C2H4O monomer of PVA selected as the ligand and the Sakacin P protein selected as the receptor was determined. Conclusion: According to the results of the analysis, the presence of a strong inhibitor was detected between the ligand and the target. Therefore, this study can serve as a template for polymer-bacteriocin materials to be produced in the laboratory.

Computational Analysis and NGS for Human LDHC Complexed with NAD+ and Ethylamino Acetic Acid (Lung Cancer)

Abstract: This study presents a multidimensional exploration of the structural and functional characteristics of the human Lactate Dehydrogenase C (LDHC) complexed with NAD+ and ethylamino acetic acid (EAA), focusing on its implications in lung cancer. Leveraging data from the Protein Data Bank (PDB) and Molecular Modeling Database (MMDB), a comprehensive analysis was conducted using various computational tools and resources. Structural insights were gained through PDBsum and RasMol, elucidating molecular interactions and identifying potential drug-target sites. Sequence analysis via BLAST and Multiple Sequence Alignment provided further understanding of conserved sequences and structural motifs. Visualization and manipulation of molecular structures were facilitated by PyMOL, enabling the identification of active drug-target sites. Proteinligand docking studies using the CB-Dock2 server assessed the efficiency of LDHC complexation with NAD+. Structural validation through the SAVES server ensured the reliability of the complex structure. Additionally, biological network analysis using the STRING database revealed associations with gene ontology and structural classification of the protein, offering insights into targeted interventions in the ancestry of the protein. This comprehensive approach provides valuable insights into LDHC's role in cancer biology and offers promising avenues for therapeutic development in lung cancer.

Molecular docking approach for the design and synthesis of new pyrazolopyrimidine analogs of roscovitine as potential CDK2 inhibitors endowed with pronounced anticancer activity

Cyclin-dependent kinase 2 (CDK2) is a vital protein for controlling cell cycle progression that is critically associated with various malignancies and its inhibition could offer a convenient therapeutic approach in designing anticancer remedies. Consequently, this study aimed to design and synthesize new CDK2 inhibitors featuring roscovitine as a template model. The purine ring of roscovitine was bioisosterically replaced with the pyrazolo[3,4-d]pyrimidine scaffold, in addition to some modifications in the side chains. A preliminary molecular docking study for the target chemotypes in the CDK2 binding domain revealed their ability to accomplish similar binding patterns and interactions to that of the lead compound roscovitine. Afterwards, synthesis of the new derivatives was accomplished. Then, the initial anticancer screening at a single dose by the NCI revealed that compounds 7a, 9c, 11c, 17a and 17b achieved the highest GI% values reaching up to 150 % indicating their remarkable activity. These derivatives were subsequently selected to undertake five-dose testing, where compounds 7a, 9c, 11c and 17a unveiled the most pronounced activity against almost the full panel with GI50 ranges; 1.41–28.2, 0.116–2.39, 0.578–60.6 and 1.75–42.4 µM, respectively and full panel GI50 (MG-MID); 8.24, 0.6, 2.46 and 6.84 µM, respectively. CDK2 inhibition assay presented compounds 7a and 9c as the most potent inhibitors with IC50 values of 0.262 and 0.281 µM, respectively which are nearly 2.4 folds higher than the reference ligand roscovitine (IC50 = 0.641 µM). Besides, flow cytometric analysis on the most susceptible and safe cell lines depicted that 7a caused cell cycle arrest at G1/S phase in renal cancer cell line (RXF393) while 9c led to cell growth arrest at S phase in breast cancer cell line (T-47D) along with pronounced apoptotic induction in the mentioned cell lines. These findings afforded new anticancer pyrazolo[3,4-d]pyrimidine, roscovitine analogs, acting via CDK2 inhibition.

In silico and in vitro study of pyrimidones synthesized with ethylenediamine- modified β-cyclodextrin: potential against ESBL E. coli

Modern organic synthesis is primarily focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-mass spectroscopy. Major highlights of the reported work include the economical atom process, remarkably gentler reaction conditions, ease of operation, high isolated yields, and excellent catalyst turnover numbers. The molecular docking studies suggest that the compound 4n has hydrogen bonding, hydrophobic and π-pair interactions with the active site of the CXT M 15 receptor. Further, the in-vitro antibacterial study as well as the screening of anti-biofilm activity resulted in a BIC value of 76.79 ± 0.785% at a concentration of 10 µg/mL and morphological alterations induced by DHPMs against the ESBL E. coli strain aggregated with a good result. KEY WORDS: Ethylenediamine modified β-CD, Multicomponent reaction, 3,4-dihydropyrimidin-2(1H)-ones DHPM derivatives, Solvent-free conditions, Reusability, Antibactercidal Bull. Chem. Soc. Ethiop. 2024, 38(4), 1103-1118. DOI: https://dx.doi.org/10.4314/bcse.v38i4.23

DFT Calculations, Molecular Docking, and Pharmacological Properties Investigation for 5-Benzoxazolecarboxylic Acid as a Target Anti-Cancer Agent

In this study, the electronic properties of the 5-Benzoxazolecarboxylic acid molecule, a benzoxazole derivative, were calculated at the DFT/B3LYP/6-311++G(d,p) level of theory. Electronic properties and chemical reactivity of the optimized structure, such as Frontier molecular orbital (FMO), global and chemical reactivity descriptors, molecular electrostatic potential (MEP), and charge analyses (APT, Hirshfeld, and NBO), were investigated. Also, electronic properties are supported by electron localization function (ELF) and localized orbital locator (LOL) analyses. Toxicity effects such as mutagenic, tumorigenic, irritant, reproductive effect, and physicochemical properties such as druglikeness and drugscore were investigated. Molecular docking studies were conducted with the vascular endothelial growth factor receptor VEGFR-2 and the PARP-2 inhibitor, which is involved in many critical cellular processes, including DNA single-stranded fracture repair and cell death control, and its effectiveness in cancer treatment was investigated.

Electrochemical Detection of Melphalan in Biological Fluids Using a g-C3N4@ND-COOH@MoSe2 Modified Electrode Complemented by Molecular Docking Studies with Cellular Tumor Antigen P53.

Melphalan (Mel) is a potent alkylating agent utilized in chemotherapy treatments for a diverse range of malignancies. The need for its accurate and timely detection in pharmaceutical preparations and biological samples is paramount to ensure optimized therapeutic efficacy and to monitor treatment progression. To address this critical need, our study introduced a cutting-edge electrochemical sensor. This device boasts a uniquely modified electrode crafted from graphitic carbon nitride (g-C3N4), decorated with activated nanodiamonds (ND-COOH) and molybdenum diselenide (MoSe2), and specifically designed to detect Mel with unparalleled precision. Our rigorous testing employed advanced techniques such as cyclic voltammetry and differential pulse voltammetry. The outcomes were promising; the sensor consistently exhibited a linear response in the range of 0.5 to 12.5 μM. Even more impressively, the detection threshold was as low as 0.03 μM, highlighting its sensitivity. To further enhance our understanding of Mel's biological interactions, we turned to molecular docking studies. These studies primarily focused on Mel's interaction dynamics with the cellular tumor antigen P53, revealing a binding affinity of -5.0 kcal/mol. A fascinating observation was made when Mel was covalently conjugated with nanodiamond-COOH (ND-COOH). This conjugation resulted in a binding affinity that surged to -10.9 kcal/mol, clearly underscoring our sensor's superior detection capabilities. This observation also reinforced the wisdom behind incorporating ND-COOH in our electrode design. In conclusion, our sensor not only stands out in terms of sensitivity but also excels in selectivity and accuracy. By bridging electrochemical sensing with computational insights, our study illuminates Mel's intricate behavior, driving advancements in sensor technology and potentially revolutionizing cancer therapeutic strategies.

Oleate Epoxides Derived from Palm Oil as New Anticancer Agents: Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies Against FASN Protein

AbstractPalm oil contains an abundant concentration of oleic acid which is known to have low toxicity to human health. The unsaturated double‐bond structure in oleic acid can be modified to synthesize oleate epoxides. The potential benefit of epoxide derivatives is their high biological activity that can be directed as new anticancer agents. In this work, the synthesis of epoxides from purified fatty acid methyl ester (EPFAME) and epoxides from purified fatty acid ethyl ester (EPFAEE) from palm oil in addition to cytotoxicity evaluations as new anticancer agents were investigated by in vitro and in silico studies. Both EPFAME and EPFAEE derivatives were successfully obtained in 82.80 % and 85.80 % yield, respectively. The MTT assay results revealed that EPFAME and EPFAEE significantly decreased the cell viability of WiDr cancer cells with IC50 of 2.70 and 14.23 μg/mL, respectively. They also showed moderate potency against T47D and HeLa cancer cell lines with IC50≥20 μg/mL. The results suggested that the addition of a methylene group from EPFAME to EPFAEE lowers cytotoxicity. A molecular docking study revealed that EPFAME and EPFAEE bind to the fatty acid synthase (FASN) protein interacting with high stability. This is represented by the binding affinity values of EPFAME and EPFAEE to FASN protein which are −7.3 and −8.1 kcal/mol, respectively. Using epoxide compounds derived from palm oil, fatty acid esters were shown to have potential medical benefits due to their low cytotoxicity and anticancer agency against several cell lines by inhibiting proliferation and inducing apoptosis of cancer cells.

Drug repurposing: identification of SARS-CoV-2 potential inhibitors by virtual screening and pharmacokinetics strategies.

The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.

Alpha-Glucosidase Inhibition, Antioxidant Activities, and Molecular Docking Study of Krom Luang Chumphon Khet Udomsak, a Thai Traditional Remedy.

Krom Luang Chumphon Khet Udomsak remedy (KKR) has traditionally been used as an alternative treatment, particularly for hyperglycemia; however, its therapeutic efficacy has not been scientifically validated. Thus, this study aims to investigate the potential inhibitory and antioxidant effects of α-glucosidase enzyme and characterize the chemical profile of KKR extracts using gas chromatography-mass spectrometry (GC-MS). The investigation highlights both KKR extracts as potent inhibitors of α-glucosidase, with the ethanolic extract of KKR (KKRE) displaying an IC50 value of 46.80 µg/mL and a noncompetitive mode of action. The combination of ethanolic and aqueous extracts of KKR (KKRE and KKRA, respectively) with acarbose exhibited a synergistic effect against the α-glucosidase. The KKRE extract displayed strong scavenging effects in the DPPH assay (IC50 156.3 µg/mL) and contained significant total phenolic (172.82 mg GAE/g extract) and flavonoid (77.41 mg QE/g extract) contents. The major component of KKRE is palmitic acid (15.67%). Molecular docking revealed that the major compounds interacted with key amino acid residues (ASP215, GLU277, HIS351, ASP352, and ARG442), which are crucial for inhibiting α-glucosidase. Notably, campesterin had a more significant influence on α-glucosidase than acarbose, with low binding energy. These findings underscore the significance of KKR in traditional medicine and suggest that it is promising treatment for diabetes mellitus. Further studies using animal model will provide valuable insights for advancing this research.

Peptidomics-based identification of antihypertensive and antidiabetic peptides from sheep milk fermented using Limosilactobacillus fermentum KGL4 MTCC 25515 with anti-inflammatory activity: in silico, in vitro, and molecular docking studies.

This study investigated the synthesis of bioactive peptides from sheep milk through fermentation with Limosilactobacillus fermentum KGL4 MTCC 25515 strain and assessed lipase inhibition, ACE inhibition, α-glucosidase inhibition, and α-amylase inhibition activities during the fermentation process. The study observed the highest activities, reaching 74.82%, 70.02%, 72.19%, and 67.08% (lipase inhibition, ACE inhibition, α-glucosidase inhibition, and α-amylase inhibition) after 48h at 37°C, respectively. Growth optimization experiments revealed that a 2.5% inoculation rate after 48h of fermentation time resulted in the highest proteolytic activity at 9.88mg/mL. Additionally, fractions with less than 3kDa of molecular weight exhibited superior ACE-inhibition and anti-diabetic activities compared to other fractions. Fermentation of sheep milk with KGL4 led to a significant reduction in the excessive production of NO, TNF-α, IL-6, and IL-1β produced in RAW 267.4 cells upon treatment with LPS. Peptides were purified utilizing SDS-PAGE and electrophoresis on 2D gels, identifying a maximum number of proteins bands ranging 10-70kDa. Peptide sequences were cross-referenced with AHTPDB and BIOPEP databases, confirming potential antihypertensive and antidiabetic properties. Notably, the peptide (GPFPILV) exhibited the highest HPEPDOCK score against both α-amylase and ACE.

Synthesis of the Carba-Analogs of the α-Pyranose and β-Pyranose Forms of Sedoheptulose 7-Phosphate and Probing the Stereospecificity of Sedoheptulose 7-Phosphate Cyclases.

Sedoheptulose 7-phosphate (SH7P) cyclases are a subset of sugar phosphate cyclases that are known to catalyze the first committed step in many biosynthetic pathways in primary and secondary metabolism. Among them are 2-epi-5-epi-valiolone synthase (EEVS) and 2-epi-valiolone synthase (EVS), two closely related SH7P cyclases that catalyze the conversion of SH7P to 2-epi-5-epi-valiolone and 2-epi-valiolone, respectively. However, how these two homologous enzymes use a common substrate to produce stereochemically different products is unknown. Two competing hypotheses have been proposed for the stereospecificity of EEVS and EVS: (1) variation in aldol acceptor geometry during enzyme catalysis, and (2) preselection of the α-pyranose or β-pyranose forms of the substrate by the enzymes. Yet, there is no direct evidence to support or rule out either of these hypotheses. Here we report the synthesis of the carba-analogs of the α-pyranose and β-pyranose forms of SH7P and their use in probing the stereospecificity of ValA (EEVS from Streptomyces hygroscopicus subsp. jinggangensis) and Amir_2000 (EVS from Actinosynnema mirum DSM 43827). Kinetic studies of the enzymes in the presence of the synthetic compounds as well as docking studies of the enzymes with the α- and β-pyranose forms of SH7P suggest that the inverted configuration of the products of EEVS and EVS is not due to the preselection of the different forms of the substrate by the enzymes.

Evaluation of In vitro anti-inflammatory activity and In-silico pharmacokinetics and molecular docking study of Horsfieldia iryaghedhi

Background: Phytochemicals are still a valuable source to develop clinically important drugs in treating chronic and acute diseases. Inflammation is a response to an injurious stimulus of the body and novel therapeutic agents are needed to alleviate the condition with minimum side effects. Aims and Objectives: To investigate in vitro anti-inflammatory activity of methanol and aqueous leaf, bark, and combination extracts of plant Horsfieldia iryaghedhi by heat-induced egg albumin denaturation method and to analyze the phytochemicals of Horsfieldia iryaghedhi for their anti-inflammatory potential against cyclooxygenase- 2 (COX-2) using molecular docking. Methodology: Matured and fully expanded fresh leaves and barks of H. iryaghedhi were collected, and the extractions were obtained cold maceration using 99.9% methanol and distilled water as solvents. A concentration series was then developed, and the anti-inflammatory activity was evaluated against Diclofenac sodium as the positive control, using the heat-induced egg albumin denaturation method. Further, selected phytochemicals were tested against COX-2 enzyme (PDB ID: 5IKR) using site-specific molecular docking with autodock vina and the binding energies and pharmacokinetic and toxicity parameters were evaluated. Results: The methanol and aqueous extracts have shown a moderate to strong concentration-dependent anti-inflammatory activity with reference to standard Diclofenac sodium (IC50 116.4 μg/ml) and Methanol bark extract exhibited potent anti-inflammatory activity compared to other extracts (IC50 293 μg/ml). Further, Methanol and aqueous extracts showed a statistically significant correlation between concentration and percentage inhibition (p&lt;0.05, R2 ≈1). The molecular docking results suggest that the phytochemicals available on the plant have possible COX-2 inhibitory activity and the compounds selected (Methyl 2,4-dihydroxy-6-methylbenzoate and N, N-Dimethyl-5-methoxy tryptamine) even got favourable toxicity and pharmacokinetic parameters confirming their drugability. Conclusion: Methanol bark extract of Horsfieldia iryaghedhi have marked in vitro anti-inflammatory activity. The results indicate a solid possibility of lead discovery of anti- inflammatory agents from the bark and leaves of Horsfieldia iryaghedhi. However, further molecular dynamics studies and in vivo tests may be required to confirm the findings.

The effects of acteoside on locomotor recovery after spinal cord injury – The role of autophagy and apoptosis signaling pathway

In the current study, we investigated the effects of acteoside as a phenylpropanoid glycoside on interaction with neurons to assesses locomotor recovery after spinal cord injury (SCI) in rats by focusing on evaluating the factors involved in autophagy, apoptosis, inflammation and oxidative stress processes. 49 Spargue-Dawley rats were prepared and divided into seven healthy and SCI groups receiving different concentrations of acteoside. After 28 days of disease induction and treatment with acteoside, a BBB score test was used to evaluate locomotor activity. Then, by preparing spinal cord cell homogenates, the expression levels of MAP1LC3A, MAP-2, glial fibrillary acidic protein (GFAP), Nrf2, Keap-1, Caspase 3 (Casp3), Bax, Bcl-2, TNF-a, IL-1B, reactive oxygen species (ROS), and malondialdehyde (MDA) were measured. Improvement of locomotor activity in SCI rats receiving acteoside was observed two weeks after the beginning of the experiment and continued until the fourth week. Both MAP1LC3A and MAP-2 were significantly up-regulated in SCI rats treated with acteoside compared to untreated SCI rats, and GFAP levels were significantly decreased in these animals. Pro-apoptotic proteins Bax and Casp3 and anti-apoptotic protein Bcl-2 were down-regulated and up-regulated, respectively, in SCI rats receiving acteoside. In addition, a significant downregulation of iNOS, TNF-α, and IL-1β and a decrease in contents of both ROS and MDA as well as increases in Nrf2 and Keap-1 were seen in rats receiving acteoside. Furthermore, acteoside strongly interacted with MAP1LC3A, TNF-α, and Casp3 targets with binding affinities of −8.3 kcal/mol, −8.3 kcal/mol, and −8.5 kcal/mol, respectively, determined by molecular docking studies. In general, it can be concluded that acteoside has protective effects in SCI and can be considered as an adjuvant therapy in the treatment of this disease. However, more studies, especially clinical studies, are needed in this field.

Identification of a cinnamoyl-CoA reductase from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis.

The identification of a functional cinnamoyl-CoA reductase enzyme from Cinnamomum cassia involved in trans-cinnamaldehyde biosynthesis offers the potential for enhancing trans-cinnamaldehyde production through genetic engineering. A significant accumulation of trans-cinnamaldehyde has been found in the bark tissues of C. cassia, used in traditional Chinese medicine. trans-Cinnamaldehyde exhibits various pharmacological properties such as anti-inflammatory, analgesic, and protection of the stomach and the digestive tract. However, further elucidation and characterization of the biosynthetic pathway for trans-cinnamaldehyde is required. In this study, we conducted an integrated analysis of trans-cinnamaldehyde accumulation profiles and transcriptomic data from five different C. cassia tissues to identify the genes involved in its biosynthesis. The transcriptome data we obtained included nearly all genes associated with the trans-cinnamaldehyde pathway, with the majority demonstrating high abundance in branch barks and trunk barks. We successfully cloned four C. cassia cinnamoyl-CoA reductases (CcCCRs), a key gene in trans-cinnamaldehyde biosynthesis. We found that the recombinant CcCCR1 protein was the only one that more efficiently converted cinnamoyl-CoA into trans-cinnamaldehyde. CcCCR1 exhibited approximately 14.7-fold higher catalytic efficiency (kcat/Km) compared to the Arabidopsis thaliana cinnamoyl-CoA reductase 1 (AtCCR1); therefore, it can be utilized for engineering higher trans-cinnamaldehyde production as previously reported. Molecular docking studies and mutagenesis experiments also validated the superior catalytic activity of CcCCR1 compared to AtCCR1. These findings provide valuable insights for the functional characterization of enzyme-coding genes and hold potential for future engineering of trans-cinnamaldehyde biosynthetic pathways.

Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

Designing Antitrypanosomal and Antileishmanial BODIPY Derivatives: A Computational and In Vitro Assessment.

Leishmaniasis and Human African trypanosomiasis pose significant public health threats in resource-limited regions, accentuated by the drawbacks of the current antiprotozoal treatments and the lack of approved vaccines. Considering the demand for novel therapeutic drugs, a series of BODIPY derivatives with several functionalizations at the meso, 2 and/or 6 positions of the core were synthesized and characterized. The in vitro activity against Trypanosoma brucei and Leishmania major parasites was carried out alongside a human healthy cell line (MRC-5) to establish selectivity indices (SIs). Notably, the meso-substituted BODIPY, with 1-dimethylaminonaphthalene (1b) and anthracene moiety (1c), were the most active against L. major, displaying IC50 = 4.84 and 5.41 μM, with a 16 and 18-fold selectivity over MRC-5 cells, respectively. In contrast, the mono-formylated analogues 2b and 2c exhibited the highest toxicity (IC50 = 2.84 and 6.17 μM, respectively) and selectivity (SI = 24 and 11, respectively) against T. brucei. Further insights on the activity of these compounds were gathered from molecular docking studies. The results suggest that these BODIPYs act as competitive inhibitors targeting the NADPH/NADP+ linkage site of the pteridine reductase (PR) enzyme. Additionally, these findings unveil a range of quasi-degenerate binding complexes formed between the PRs and the investigated BODIPY derivatives. These results suggest a potential correlation between the anti-parasitic activity and the presence of multiple configurations that block the same site of the enzyme.

In silico Analysis of 1,3,4-Oxadiazoles as Potential BCL-2 Inhibitor for Cancer Treatment

The possible efficacy of 1,3,4-oxadiazoles as B-cell lymphoma 2 (BCL-2) inhibitors for cancer treatment is investigated in this study using in silico approaches such as molecular docking, ADME and toxicity prediction. Molecular docking studies predict the binding affinities and binding modes of a series of 1,3,4-oxadiazole derivatives with the BCL-2 protein. The results revealed that the compounds with strong interactions and favourable binding modes, indicating their potential as BCL-2 inhibitors. An ADMET analysis assesses the pharmacokinetic properties and potential toxicity of the identified compounds. Parameters such as absorption, distribution, metabolism, excretion and toxicity (ADMET) were evaluated to predict the suitability of these 1,3,4-oxadiazoles as drug candidates for cancer therapy. The integration of molecular docking and ADMET analysis data led to the identification and prioritization of lead compounds with potent BCL-2 inhibitory activity and favourable pharmacokinetic profiles. This research contributes to the on-going efforts in drug discovery, emphasizing the potential of 1,3,4-oxadiazoles as a class of compounds with significant anticancer properties through BCL-2 inhibition.

COX inhibitory profiles of a series of thiadiazole-benzothiazole hybrids

In an endeavour to identify small molecule COX-1 inhibitors, a colorimetric assay protocol was applied for the in vitro evaluation of COX-1 and 2 inhibitory potential of a series of thiadiazole-benzothiazole hybrids. The most potent and selective COX-1 inhibitor in this series was found as 2-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-N-(6-chlorobenzothiazol-2-yl)acetamide (7) (51.36 ± 3.32% at 100 µM) compared to SC-560 (83.64 ± 3.76% at 1 µM). Compound 7 exerted weaker inhibitory effect on COX-2 (11.05 ± 1.69% at 100 µM). To explore its binding interactions at the active site of human COX-1 (PDB ID: 6Y3C), molecular docking studies were conducted. Compound 7 could establish hydrogen bonds with proper residues thanks to its amide C=O group. In silico studies were employed to shed light on their pharmacokinetic properties. Taken together, compound 7 can be considered as a potential lead compound for the generation of selective COX-1 inhibitors with enhanced efficacy.

Synthesis, In Silico Prediction, and In Vitro Evaluation of Anti-tumor Activities of Novel 4'-Hydroxybiphenyl-4-carboxylic Acid Derivatives as EGFR Allosteric Site Inhibitors.

Allosteric inhibition of EGFR Tyrosine Kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies. A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, 1HNMR, 13CNMR, and HR-mass spectroscopy. Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC50 value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity. Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.