Phosphoinositide 3-kinase (PI3K) enzymes are important drug targets, especially in oncology, and several inhibitors are currently under investigation in clinical trials for the treatment of ...lymphocytic leukemia, follicular lymphoma, breast, thyroid, colorectal, and lung cancer. Targeted covalent inhibitors hold significant promise for drug discovery research especially for kinases. Targeting the lysine residues attracts attention as a new strategy in designing targeted covalent inhibitors, since the lysine residue provides several advantages over the traditional cysteine residue. Recently, new highly selective covalent inhibitors of PI3Kδ with activated ester warheads, targeting the conserved Lys779 residue, were reported. Based on the observed kinetics, a covalent inhibition mechanism was proposed, but the atomistic details of the reaction are still not understood. Therefore, in the present work, we have conducted quantum chemical ONIOM M06-2X/6-31+G(d,p):PM6 calculations on the active site cluster structure of PI3Kδ to elucidate the microscopic details of the mechanism of the aminolysis reaction between Lys779 and the ester inhibitors. Our calculations clearly discriminate the noncovalent methyl ester inhibitor and the covalent inhibitors with activated phenolic esters. For the representative
-NO
,
-F,
-H, and
-OCH
phenolic esters, the Gibbs free energy profiles of alternative mechanistic paths through either Asp782 or Asp911 demonstrate the modulatory role of active site aspartate residues. The most plausible path alters depending on the electron-withdrawing/donating nature of the
-substituted phenolate leaving group. Inhibitors with sufficiently strong electron-withdrawing group prefer direct dissociation of the leaving group from the tetrahedral zwitterion intermediate, while the ones with electron-donating group favor the formation of a neutral tetrahedral intermediate prior to the dissociation. The relative Gibbs free energy barriers of
-NO
<
-
<
-H <
-OCH
substituted phenyl esters display the same qualitative trend as the experimentally measured
/
values. Our results provide in depth insight into the mechanism, which can pave the way for optimizing the inhibitor efficiency.
Fullerene derivatives (FDs) are widely used in nanomaterials production, the pharmaceutical industry and biomedicine. In the present study, we focused on the potential toxic effects of FDs on the ...aquatic environment. First, we analyzed the binding affinity of 169 FDs to 10 human proteins (1D6U, 1E3K, 1GOS, 1GS4, 1H82, 1OG5, 1UOM, 2F9Q, 2J0D, 3ERT) obtained from the Protein Data Bank (PDB) and showing high similarity to proteins from aquatic species. Then, the binding activity of 169 FDs to the enzyme acetylcholinesterase (AChE)—as a known target of toxins in fathead minnows and Daphnia magna, causing the inhibition of AChE—was analyzed. Finally, the structural aquatic toxicity alerts obtained from ToxAlert were used to confirm the possible mechanism of action. Machine learning and cheminformatics tools were used to analyze the data. Counter-propagation artificial neural network (CPANN) models were used to determine key binding properties of FDs to proteins associated with aquatic toxicity. Predicting the binding affinity of unknown FDs using quantitative structure–activity relationship (QSAR) models eliminates the need for complex and time-consuming calculations. The results of the study show which structural features of FDs have the greatest impact on aquatic organisms and help prioritize FDs and make manufacturing decisions.
The one-pot reaction of chlorosulfonyl isocyanate (CSI) with epoxides having phenyl, benzyl and fused cyclic alkyl groups in different solvents under mild reaction conditions without additives and ...catalysts was studied. Oxazolidinones and five-membered cyclic carbonates were obtained in ratios close to 1:1 in the cyclization reactions. The best yields of these compounds were obtained in dichloromethane (DCM). Together with 16 known compounds, two novel oxazolidinone derivatives and two novel cyclic carbonates were synthesized with an efficient and straightforward method. Compared to the existing methods, the synthetic approach presented here provides the following distinct advantageous: being a one-pot reaction with metal-free reagent, having shorter reaction times, good yields and a very simple purification method. Moreover, using the density functional theory (DFT) method at the M06-2X/6-31+G(d,p) level of theory the mechanism of the cycloaddition reactions has been elucidated. The further investigation of the potential energy surfaces associated with two possible channels leading to oxazolidinones and five-membered cyclic carbonates disclosed that the cycloaddition reaction proceeds via an asynchronous concerted mechanism in gas phase and in DCM.
A series of 3-aryl coumarin derivatives and 3-phenylazo-4-hydroxycoumarin were evaluated for their monoamine oxidase (MAO) A and B inhibitory activity and selectivity by fluorometric enzymological ...assays. Among 21 coumarin derivatives, compound
21
(3-phenylazo-4-hydroxycoumarin) displayed a good inhibitory activity (0.12 ± 0.02 µM) and very high selectivity for MAO-B (SI > 833.33). The inhibition was determined as mixed-type and not time-dependent. Docking studies, molecular dynamics and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculations were performed to elucidate
in vitro
results. Our results reveal that the insertion of an azo linker between coumarin and phenyl rings in 3-arylcoumarins enhances MAO-B selectivity enormously since such a linker leads to the perfect alignment of the coumarin ring in the aromatic cage and the phenyl ring in the entrance cavity of MAO-B active site. Hydrogen bond interactions with Cys172 in the active site entrance of MAO-B also contributes to the remarkably higher inhibitory activity and selectivity for MAO-B.
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•Five proteins related to diabetic disease were selected from Protein Data Bank.•Binding scores were calculated for five proteins with 169 fullerene derivatives.•Correlation between ...drug-like descriptors and binding scores activity was examined.•The contribution of descriptors to protein-ligand binding was demonstrated.•The QSARs models for prediction of binding scores activity were built.
Fullerene derivatives (FDs) belong to a relatively new family of nano-sized organic compounds. They are widely applied in materials science, pharmaceutical industry, and (bio) medicine. This research focused on the study of FDs in terms of their potential inhibitory effect on therapeutic targets associated with diabetic disease, as well as analysis of protein–ligand binding in order to identify the key binding characteristics of FDs.
Therapeutic drug compounds when entering the biological system usually inevitably encounter and interact with a vast variety of biomolecules that are responsible for many different functions in organisms. Protein biomolecules are the most important functional components and used in this study as target structures. The structures of proteins (PDB ID: 1BMQ, 1FM6, 1GPB, 1H5U, 1US0) belonging to the class of anti-diabetes targets were obtained from the Protein Data Bank (PDB). Protein binding activity data (binding scores) were calculated for the dataset of 169 FDs related to these five proteins. Subsequently, the resulting data were analyzed using various machine learning and cheminformatics methods, including artificial neural network algorithms for variable selection and property prediction.
The Quantitative Structure-Activity Relationship (QSAR) models for prediction of binding scores activity were built up according to five Organization for Economic Co-operation and Development (OECD) principles.
All the data obtained can provide important information for further potential use of FDs with different functional groups as promising medical antidiabetic agents. Binding scores activity can be used for ranking of FDs in terms of their inhibitory activity (pharmacological properties) and potential toxicity.
Tolmetin hydrazide and a novel series of tolmetin hydrazide–hydrazones 4a–l were synthesized in this study. The structures of the new compounds were determined by spectral (FT‐IR, 1H NMR) methods. ...N′‐(2,6‐Dichlorophenyl)methylidene‐2‐1‐methyl‐5‐(4‐methylbenzoyl)‐1H‐pyrrol‐2‐ylacetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT‐116 (ATCC, CCL‐247) and HT‐29 (ATCC, HTB‐38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti‐cancer activity with an IC50 value of 76 μM against colon cancer line HT‐29 (ATCC, HTB‐38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase‐3, caspase‐8, caspase‐9, and annexin‐V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti‐cancer activity of this compound was due to the activation of caspase‐8 and caspase‐9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT‐29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site.
The tolmetin hydrazone N′‐(2,6‐dichlorophenyl)methylidene‐2‐1‐methyl‐5‐(4‐methylbenzoyl)‐1H‐pyrrol‐2‐ylacetohydrazide (4g) exhibited anticancer activity with an IC50 value of 76 µM against HT‐29 cells and did not display cytotoxicity toward control fibroblast cells, compared to tolmetin. The anti‐cancer activity of 4g was shown to be due to the activation of caspase‐8 and caspase‐9 involved in apoptosis.
Monoamine oxidases are two isozymic flavoenzymes which are the important targets for drugs used in the treatment of depression, Parkinson and Alzheimer’s diseases. The catalytic reaction taking place ...between the cofactor FAD and amine substrate is still not completely understood. Herein we employed quantum chemical methods on the recently proposed direct hydride transfer mechanism including full active site residues of MAO isoforms in the calculations. Activation free energy barriers of direct hydride transfer mechanism for MAO-A and MAO-B were calculated by ONIOM (our own
n
-layered integrated molecular orbital + molecular mechanics) method with QM/QM (quantum mechanics:quantum mechanics) approach employing several density functional theory functionals, B3LYP, WB97XD, CAM-B3LYP and M06-2X, for the high layer. The formation of very recently proposed αC–flavin N5 adduct inside the enzyme has been investigated. ONIOM (M06-2X/6-31+G(d,p):PM6) results revealed that such an adduct may form only in MAO-B suggesting slightly different hydride transfer mechanisms for MAO-A and MAO-B.
The pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of ...5H-pyrrolo2,1-d1,2,5triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo1,2-apyrazin-1(2H)-one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo2,1-d1,2,5triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.
In this study, we have synthesized a series of 3‐(pyridin‐2‐yl)‐2‐(pyridin‐2‐ylimino)thiazolidin‐4‐ol derivatives regioselectively from 2‐iminothiazolidin‐4‐ones using LiAlH4 at room temperature. Due ...to the presence of the restricted rotation around the N3‐Caryl single bond, the formation of M/P isomers was observed. The OH group of the hemiaminal was found to orient itself on the same side with pyridyl nitrogen during this restricted rotation to form an intramolecular hydrogen bond, which was demonstrated by the computational DFT study. This orientation presumably inhibited the occurrence of dehydration and stabilized the molecule.
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