From farm to pharma: Investigation of the therapeutic potential of the dietary plants Apium graveolens L., Coriandrum sativum, and Mentha longifolia, as AhR modulators for Immunotherapy.

Autoimmune diseases represent a complex array of conditions where the body's immune system mistakenly attacks its own tissues. These disorders, affecting millions worldwide, encompass a broad spectrum of conditions ranging from rheumatoid arthritis and multiple sclerosis to lupus and type 1 diabetes. The Aryl hydrocarbon receptor (AhR) translocator, expressed across immune and other cell types, plays crucial roles in immune disorders and inflammatory diseases. With a realm towards natural remedies in modern medicine for disease prevention, this study investigates the electronic properties and behaviors of bioactive compounds from dietary sources, including Apium graveolens L. (Celery), Coriandrum sativum seeds (Coriander), and Mentha longifolia, as AhR modulators. Through comprehensive analysis (HOMO-LUMO, ESP, LOL, and ELF), electron-rich and -poor regions, electron localization, and delocalization are identified, contrasting these compounds with the toxic AhR ligand, TCDD. Evaluation of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties reveals favorable pharmacokinetics without blood-brain barrier penetration, indicating drug-like characteristics. Molecular docking demonstrates stronger interactions of dietary flavonoid ligands with AhR transcription compared to TCDD. Molecular dynamics simulations confirm the stability of complexes and the sustainability of interactions formed. This research underscores the potential of natural compounds as effective AhR modulators for therapeutic interventions in immune-related disorders.

Design of novel isoxazole derivatives as tubulin inhibitors using computer-aided techniques: QSAR modeling, in silico ADMETox, molecular docking, molecular dynamics, biological efficacy, and retrosynthesis.

In the current work, computational methods were used to investigate new isoxazole derivatives that could be used as tubulin inhibitors. The study aims to develop a reliable quantitative structure-activity relationship (QSAR) model, following the criteria set by Golbraikh, Tropsha, and Roy. As a result, seven candidate compounds were developed, all having higher activity than the well-established anticancer agent Cisplatin (Cisp). According to the ADMETox in silico test, the candidates Pr4, Pr5, and P6 can be toxic. As a result, we have chosen to focus our study on compounds Pr1, Pr2, and Pr3. Molecular docking analysis revealed that drug candidate Pr2 exhibits the highest stability within the oxidized quinone reductase 2 (PDB ID: 4zvm), target receptor (ΔG(Pr2) = ΔG(Pr3) = -10.4 < ΔG(Pr1) = -10.0 < ΔG(Cisp) = -7.3 kcal/mol). This finding aligns with the activity predictions made by the QSAR model. Furthermore, molecular dynamics simulations of the Pr2-4zvm complex over 100 ns confirm the ligand's robust stability within the receptor's active site, supporting the results obtained from molecular docking and the QSAR model predictions. The CaverDock software was utilized to identify the tunnels likely to be followed by ligands moving from the active site to the receptor surface. This analysis also helped in determining the biological efficacy of the target compounds. The results indicated that the Pr2 compound is more effective than the others. Finally, the computer-assisted retrosynthesis process of two high confidence sequences was used to synthesize drug candidates.Communicated by Ramaswamy H. Sarma.

3D-QSAR methods were used to design eight new compounds and anti-tubulin agents.3D-QSAR models were validated by Golbraikh­Tropsha and Roy methods.The toxicity and pharmacokinetics of the proposed compounds were identified by the Lipinski rule of five, Veber rules, and ADMETox.Pr2 and Pr3 had a reasonable affinity to the receptor protein (ID PDB: 4zvm) based on molecular docking, reactivity indices, and molecular dynamics simulation.Metadynamics was used to study ligand transport in the receptor (ID PDB:3zvm).

In silico research on new sulfonamide derivatives as BRD4 inhibitors targeting acute myeloid leukemia using various computational techniques including 3D-QSAR, HQSAR, molecular docking, ADME/Tox, and molecular dynamics.

Acute myeloid leukemia, a serious condition affecting stem cells, drives uncontrollable myeloblast proliferation, leading to accumulation. Extensive research seeks rapid, effective chemotherapeutics. A potential option is a BRD4 inhibitor, known for suppressing cell proliferation. Sulfonamide derivatives probed essential structural elements for potent BRD4 inhibitors. To achieve this goal, we employed 3D-QSAR molecular modeling techniques, including CoMFA, CoMSIA, and HQSAR models, along with molecular docking and molecular dynamics simulations. The validation of the 2D/3D QSAR models, both internally and externally, underscores their robustness and reliability. The contour plots derived from CoMFA, CoMSIA, and HQSAR analyses played a pivotal role in shaping the design of effective BRD4 inhibitors. Importantly, our findings highlight the advantageous impact of incorporating bulkier substituents on the pyridinone ring and hydrophobic/electrostatic substituents on the methoxy-substituted phenyl ring, enhancing interactions with the BRD4 target. The interaction mode of the new compounds with the BRD4 receptor (PDB ID: 4BJX) was investigated using molecular docking simulations, revealing favorable binding energies, supported by the formation of hydrogen and hydrophobic bonds with key protein residues. Moreover, these novel inhibitors exhibited good oral bioavailability and demonstrated non-toxic properties based on ADMET analysis. Furthermore, the newly designed compounds along with the most active one from series 58, underwent a molecular dynamics simulation to analyze their behavior. The simulation provided additional evidence to support the molecular docking results, confirming the sustained stability of the analyzed molecules over the trajectory. This outcome could serve as a valuable reference for designing and developing novel and effective BRD4 inhibitors.Communicated by Ramaswamy H. Sarma.

Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques.

A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA (Q2 = 0.689; R = 0.999; R2pred = 0.986), CoMSIA (Q2 = 0.614; R2 = 0.923; R2pred = 0.815) and HQSAR (Q2= 0.603; R2 = 0.662; R2pred = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC50 inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma.

3D QSAR studies, molecular docking and ADMET evaluation, using thiazolidine derivatives as template to obtain new inhibitors of PIM1 kinase.

Proviral Integration site for Moloney murine leukemia virus-1 (PIM1) belongs to the serine/threonine kinase family of Ca2+-calmodulin-dependent protein kinase (CAMK) group, which is involved in cell survival and proliferation as well as a number of other signal transduction pathways. Thus, PIM1 is regarded as a promising target for treatment of cancers. In the present paper, a three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking were performed to investigate the binding between PIM1 and thiazolidine inhibitors in order to design potent inhibitors. The comparative molecular similarity indices analysis (CoMSIA) was developed using twenty-six molecules having pIC50 ranging from 8.854 to 6.011 (IC50 in nM). The best CoMSIA model gave significant statistical quality. The determination coefficient (R2) and Leave-One-Out cross-validation coefficient (Q2) are 0.85 and 0.58, respectively. Furthermore, the predictive ability of this model was evaluated by external validation((n = 11, R2test = 0.72, and MAE = 0.170 log units). The graphical contour maps could provide structural features to improve inhibitory activity. Furthermore, a good consistency between contour maps and molecular docking strongly demonstrates that the molecular modeling is reliable. Based on these satisfactory results, we designed several new potent PIM1 inhibitors and their inhibitory activities were predicted by the molecular models. Additionally, those newly designed inhibitors, showed promising results in the preliminary in silico ADMET evaluations, compared to the best inhibitor from the studied dataset. The results expand our understanding of thiazolidines as inhibitors of PIM1 and could be of great help in lead optimization for early drug discovery of highly potent inhibitors.

Computer aided drug design based on 3D-QSAR and molecular docking studies of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives as PIM2 inhibitors: a proposal to chemists.

PIM2 kinase plays a crucial role in the cell cycle events including survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Thus, it is regarded as an essential target for cancer pharmaceutical. Design of novel 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives with enhanced PIM2 inhibitory activity. A series of twenty-five PIM2 inhibitors reported in the literature containing 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines scaffold was studied by using two computational techniques, namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indexes analysis (CoMSIA) studies were developed using nineteen molecules having pIC50 ranging from 8.222 to 4.157. The best generated CoMFA and CoMSIA models exhibit conventional determination coefficients R2 of 0.91 and 0.90 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.68 and 0.62, respectively. Moreover, the predictive ability of those models was evaluated by the external validation using a test set of six compounds with predicted determination coefficients Rtest 2 of 0.96 and 0.96, respectively. Besides, y-randomization test was also performed to validate our 3D-QSAR models. The most and the least active compounds were docked into the active site of the protein (PDB ID: 4 × 7q) to confirm those obtained results from 3D-QSAR models and elucidate the binding mode between this kind of compounds and the PIM2 enzyme. These satisfactory results are not offered help only to understand the binding mode of 5-(1H-indol-5-yl)-1,3,4-thiadiazol series compounds into this kind of targets, but provide information to design new potent PIM2 inhibitors.

(+)- and (-)-2-aminocyclobutane-1-carboxylic acids and their incorporation into highly rigid beta-peptides: stereoselective synthesis and a structural study.

[Chemical reaction: See text] Several derivatives of (+)- and (-)-2-aminocyclobutane-1-carboxylic acid, 1, have been prepared through enantiodivergent synthetic sequences. The stereoselective synthesis of free amino acid (+)-1 has been achieved, and this product has been fully characterized for the first time. Stereocontrolled alternative synthetic methodologies have been developed for the preparation of bis(cyclobutane) beta-dipeptides in high yields. Among them, enantio and diastereomers have been synthesized. beta,beta- and beta,delta-Dimers resulting from the coupling of a cyclobutane residue and a linear amino acid have also been prepared. The ability of the cyclobutane ring as a structure-promoting unit both in the monomers and in the dimers has been manifested. The NMR structural study and DFT theoretical calculations evidence the formation of strong intramolecular hydrogen bonds giving rise to cis-fused [4.2.0]octane structural units that confer high rigidity on these molecules both in solution and in the gas phase. The contribution of a cis-trans conformational equilibrium derived from the rotation around the carbamate N-C(O) bond has also been observed, the trans form being the major conformer. In the solid state, this equilibrium does not exist, and moreover, intermolecular hydrogen bonds are present.