Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease.

The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on- andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease-modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the ß-amyloid precursor protein (ßAPP) and ß-amyloid (Aß) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

Theoretical study of CO2 hydrogenation into formic acid on Lewis acid zeolites.

Conversion of carbon dioxide (CO2) to more valuable chemicals is nowadays receiving increasing attention from an environmental and industrial point of view. Herein, we computationally investigated CO2 hydrogenation to formic acid on Lewis acid zeolites by means of density functional theory (DFT) with the M06-L functional. The reaction proceeds in two steps, hydrogenation of CO2 to form the formate intermediate and hydrogen-abstraction to form formic acid. A defect zeolite seems to be favored over a perfect one, leading to its low rate determining step barrier of 5.2 kcal mol-1. We also considered the effect of the zeolite frameworks and found that the catalytic activities are in the order Sn-ZSM-5 > Sn-BEA > Sn-FAU. Finally, we performed catalytic activity screenings of tetravalent metals (Ge, Zr and Hf) substituted into the defect Sn-ZSM-5 zeolite. The order Hf > Zr > Sn > Ge was found based on the rate determining step activation energy. The difference in activation energy can be explained by the difference in charge transfer from the catalytic site to the reacting molecules.

Structure-guided cancer blockade between bioactive bursehernin and proteins: Molecular docking and molecular dynamics study.

Bursehernin (5'-desmethoxyyatein) is a natural lignan, which has anti-tumor activity in vitro. In this study, the binding-inhibitory effects of bursehernin were screening on selected 80 proteins associated with cancer pathway. The computational analysis suggested inhibitory effect due to bursehernin towards proteins related to cancer proliferation, including FMS kinase receptor, heat shock protein 90-α (Hsp90-α), adenylate cyclase 10 (ADCY10), mitogen-activated protein kinase kinase (MEK1), and α-tubulin. Moreover, bursehernin could interfere with cell cycle progression via binding to cyclin B proteins. Among all screened proteins, the compound showed an interesting binding affinity to the FMS kinase receptor. The binding mode studies by molecular dynamic technique showed that aromatic ring of bursehernin compound was responsible for compound-protein interaction through pi-pi stacking with Tyr105 and Phe178 of the FMS kinase receptor. This study suggests that bursehernin has potential for development as an anti-tumor agent with an anti-proliferation, and cell cycle arrest inducing, although further studies are needed.

Ethylene Epoxidation with Nitrous Oxide over Fe-BTC Metal-Organic Frameworks: A DFT Study.

The epoxidation of ethylene with N2 O over the metal-organic framework Fe-BTC (BTC=1,3,5-benzentricarboxylate) is investigated by means of density functional calculations. Two reaction paths for the production of ethylene oxide or acetaldehyde are systematically considered in order to assess the efficiency of Fe-BTC for the selective formation of ethylene oxide. The reaction starts with the decomposition of N2 O to form an active surface oxygen atom on the Fe site of Fe-BTC, which subsequently reacts with an ethylene molecule to form an ethyleneoxy intermediate. This intermediate can then be selectively transformed either by 1,2-hydride shift into the undesired product acetaldehyde or into the desired product ethylene oxide by way of ring closure of the intermediate. The production of ethylene oxide requires an activation energy of 5.1 kcal mol-1 , which is only about one-third of the activation energy of acetaldehyde formation (14.3 kcal mol-1 ). The predicted reaction rate constants for the formation of ethylene oxide in the relevant temperature range are approximately 2-4 orders of magnitude higher than those for acetaldehyde. Altogether, the results suggest that Fe-BTC is a good candidate catalyst for the epoxidation of ethylene by molecular N2 O.

Comparison of Cu-ZSM-5 zeolites and Cu-MOF-505 metal-organic frameworks as heterogeneous catalysts for the Mukaiyama aldol reaction: a DFT mechanistic study.

The density functional theory (DFT) model ONIOM(M06L/6-311++G(2df,2p):UFF was employed to reveal the catalytic activity of Cu(II) in the paddle-wheel unit of the metal-organic framework (MOF)-505 material in the Mukaiyama aldol reaction compared with the activity of Cu-ZSM-5 zeolites. The aldol reaction between a silyl enol ether and formaldehyde catalyzed by the Lewis acidic site of both materials takes place through a concerted pathway, in which the formation of the CC bond and the transfer of the silyl group occurs in a single step. MOF-505 and Cu-ZSM-5 are predicted to be efficient catalysts for this reaction as they strongly activate the formaldehyde carbonyl carbon electrophile, which leads to a considerably lower reaction barrier compared with the gas-phase system. Both MOF-505 and Cu-ZSM-5 catalysts stabilize the reacting species along the reaction coordinate, thereby lowering the activation energy, compared to the gas-phase system. The activation barriers for the MOF-505, Cu-ZSM-5, and gas-phase system are 48, 21, and 61 kJ mol(-1) , respectively. Our results show the importance of the enveloping framework by stabilizing the reacting species and promoting the reaction.

Formaldehyde encapsulated in lithium-decorated metal-organic frameworks: a density functional theory study.

The stability of monomeric formaldehyde encapsulated in the lithium-decorated metal-organic framework Li-MOF-5 was investigated by means of density functional calculations with the M06-L functional and the 6-31G(d,p) basis set. To assess the efficiency of Li-MOF-5 for formaldehyde preservation, we consider the reaction kinetics and the thermodynamic equilibrium between formaldehyde and its trimerized product, 1,3,5-trioxane. We propose that trimerization of encapsulated formaldehyde takes place in a single reaction step with an activation energy of 34.5 kcal mol(-1). This is 17.2 kcal mol(-1) higher than the corresponding activation energy in the bare system. In addition, the reaction energy of the system studied herein is endothermic by 6.1 kcal mol(-1) and the Gibbs free energy (ΔG) of the reaction becomes positive (11.0 kcal mol(-1)). Consequently, the predicted reverse rate for the trimerization reaction in the Li-MOF-5 is significantly faster than the forward rate. The calculations show that the oligomerization of formaldehyde in Li-MOF-5 is a reversible reaction, suggesting that such a zeolite might be a good candidate material for preserving formaldehyde in its monomeric form.

Effects of the zeolite framework on the adsorptions and hydrogen-exchange reactions of unsaturated aliphatic, aromatic, and heterocyclic compounds in ZSM-5 zeolite: a combination of perturbation theory (MP2) and a newly developed density functional theory (M06-2X) in ONIOM scheme.

The confinement effect on the adsorption and reaction mechanism of unsaturated aliphatic, aromatic and heterocyclic compounds on H-ZSM-5 zeolite has been investigated by the four ONIOM methods (MP2:M06-2X), (MP2:B3LYP), (MP2:HF), and (MP2:UFF). The H-ZSM-5 'nanoreactor' porous intersection, where chemical reactions take place, is represented by a quantum cluster of 34 tetrahedral units. Ethene, benzene, ethylbenzene, and pyridine are chosen to represent reactions of various adsorbates of aliphatic, aromatic and heterocyclic compounds. Among the four combined methods, (MP2:M06-2X) outperforms the others. The results confirm that the method that takes weak interactions, especially the van der Waals interaction, into account is essential for describing the confinement effect from the zeolite framework. The effects of the infinite zeolitic framework on the cluster model are also included by a set of point charges generated by the embedded ONIOM model. The energies for the adsorption of ethene, benzene, ethylbenzene, and pyridine on H-ZSM-5 from an embedded ONIOM(MP2:M06-2X) calculation are predicted to be -14.0, -19.8, -24.7, and -48.4 kcal/mol, respectively, which are very close to available experimental observations. The adsorption energy of pyridine agrees well with the experiment data of -47.6 kcal/mol. We also applied the same computational methodology on the systematic investigation of the H/H exchange reaction of benzene and ethylbenzene with the acidic H-ZSM-5 zeolite. The H/H exchange reaction was found to take place in a single concerted step. The calculated apparent activation energies for benzene and ethylbenzene are 12.6 and 4.9 kcal/mol, which can be compared to the experimental estimates of 11.0 and 6.9 kcal/mol, respectively. The confinement effect of the extended zeolite framework has been clearly demonstrated not only to stabilize the adsorption complexes but also to improve their corresponding activation energies to approach the experimental benchmark.