Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti-protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre-clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition-state inhibitors, mechanism-based inhibitors, relevant natural products, and major patent disclosures.

: Glycolysis is a tightly regulated process in which several enzymes, such as Hexokinases (HKs), play crucial roles. Cancer cells are characterized by specific expression levels of several isoenzymes in different metabolic pathways and these features offer possibilities for therapeutic interventions. Overexpression of HKs (mostly of the HK2 isoform) have been consistently reported in numerous types of cancer. Moreover, deletion of HK2 has been shown to decrease cancer cell proliferation without explicit side effects in animal models, which suggests that targeting HK2 is a viable strategy for cancer therapy. HK2 inhibition causes a substantial decrease of glycolysis that affects multiple pathways of central metabolism and also destabilizes the mitochondrial outer membrane, ultimately enhancing cell death. Although glycolysis inhibition has met limited success, partly due to low selectivity for specific isoforms and excessive side effects of the reported HK inhibitors, there is ample ground for progress. : The current review is focused on HK2 inhibition, envisaging the development of potent and selective anticancer agents. The information on function, expression, and activity of HKs is presented, along with their structures, known inhibitors, and reported effects of HK2 ablation/inhibition. The structural features of the different isozymes are discussed, aiming to stimulate a more rational approach to the design of selective HK2 inhibitors with appropriate drug-like properties. Particular attention is dedicated to a structural and sequence comparison of the structurally similar HK1 and HK2 isoforms, aiming to unveil differences that could be explored therapeutically. Finally, several additional catalytic- and non-catalytic roles on different pathways and diseases, recently attributed to HK2, are reviewed and their implications briefly discussed.

The hydration of the hydroxyl OH radical has been investigated by microsolvation modeling and statistical mechanics Monte Carlo simulations. The microsolvation approach was based on density functional theory ͑DFT͒ calculations for OH-(H 2 O) 1-6 and (H 2 O) 1-7 clusters. The results from microsolvation indicate that the binding enthalpies of the OH radical and water molecule to small water clusters are similar. Monte Carlo simulations predict that the hydration enthalpy of the OH radical, ⌬ hyd H(OH,g), is Ϫ39.1 kJ mol Ϫ1. From this value we have estimated that the band gap of liquid water is 6.88 eV, which is in excellent agreement with the result of Coe et al. ͓J. Chem. Phys. 107, 6023 ͑1997͔͒. We have compared the structure of the hydrated OH solution with the structure of pure liquid water. The structural differences between the two systems reflect the strong role played by the OH radical as a proton donor in water. From sequential Monte Carlo/DFT calculations the dipole moment of the OH radical in liquid water is 2.2Ϯ0.1 D, which is ϳ33% above the experimental gas phase value ͑1.66 D͒.

Time-resolved photoacoustic calorimetry (TR-PAC) and quantum chemistry calculations were used to investigate the energetics of sulfur-hydrogen bonds in thiophenol and four para-substituted thiophenols, 4-XC 6 H 4 SH (X ) CH 3 , OCH 3 , Cl, and CF 3 ). The result obtained for the PhS-H gas-phase bond dissociation enthalpy, derived from the PAC experimental results in solution, is 349.4 ( 4.5 kJ mol -1 . This value is significantly higher than recent literature values but agrees with a value suggested some 20 years ago in a widely used review. The PAC result also concurs with the value computed at a high theory level, G3(MP2), 346.8 kJ mol -1 . The data obtained for the substituted thiophenols support the idea that substituent effects are less pronounced on the S-H bond dissociation enthalpy than on the O-H bond dissociation enthalpy of the corresponding phenols. † Part of the special issue "Jack Beauchamp Festschrift".

The modulation of immune checkpoint receptors has been one of the most successful, exciting, and explored approaches for cancer immunotherapy. Currently, several immune checkpoint modulators, mainly monoclonal antibodies, are showing remarkable results. However, the failure to show a response in most patients and the induction of severe immune-related adverse effects are the major drawbacks. Novel approaches concerning the development of immune modulatory small molecules have emerged as an alternative. Nevertheless, the lack of structural information about immune checkpoint receptors has hindered the rational design of those small-molecule modulators by preventing the use of methodologies such as computer-aided drug design. Herein, we provide an overview and critical analysis of the structural and dynamic details of immune checkpoint receptors (cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and glucocorticoid-induced TNFR-related protein (GITR)) and their interaction with known modulators. This knowledge is essential to advance the understanding of their binding mode and guide the design of novel effective targeted anticancer medicines.

The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John's wort, has led to the proposal that it can be utilized in photodynamic therapy. Structurally modified derivatives are at the present time being investigated to generate a more effective hypericin photosensitizer. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation is still fully understood. In the present work, molecular dynamics simulations have been performed to study the properties and the permeability of hypericin and modifications thereof, substituted with one or four bromine atoms, in a dipalmitoylphosphatidylcholine lipid membrane. The molecules were found to accumulate in the most dense region of the lipids due to competing interactions with the hydrophobic lipid interior and the polar aqueous environment. This was confirmed by analyzing the radial distribution functions and by the density profiles of the system components. Calculated free energy profiles display large negative changes in free energy for the transport process of the molecules into the lipids, which also support this finding. Permeability coefficients show overall fastest diffusion in the membrane system for hypericin containing one bromine.

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Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive study of pharmacophore definitions of features was performed in order to obtain a new improved four-point pharmacophore able to detect literature and in-house modulators and simultaneously specific enough to avoid the detection of most nonactive molecules in a universe of 152 (literature), 74 (in-house), and 46 (inactive) molecules. This pharmacophore detects 84.2% of the molecules described in the literature, along with 100% detection of in-house isolated compounds and 19.5% of false positives. The importance of the hydrophobic and electron acceptor moieties as essential features for recognition of different molecules by the P-gp drug-binding site is clarified. The best combination of acceptor, donor, hydrophobic, and aromatic characteristics that contribute for the increased selectivity shown by the described pharmacophore is evaluated, and the protonation state of the molecules is also addressed.