Influence of pH on indole-dependent heterodimeric interactions between Anopheles gambiae odorant-binding proteins OBP1 and OBP4.

Insect Odorant Binding Proteins (OBPs) constitute important components of their olfactory apparatus, as they are essential for odor recognition. OBPs undergo conformational changes upon pH change, altering their interactions with odorants. Moreover, they can form heterodimers with novel binding characteristics.

Losartan Interactions with 2-Hydroxypropyl-β-CD.

Losartan potassium salt (LSR) is a well-known antihypertensive drug with proven beneficial effects on human health. Its formulation with the non-toxic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) could improve its pharmacological profile. Thus, its molecular interactions are studied using a combination of Differential Scanning Calorimetry (DSC), Nuclear Magnetic Resonance (NMR) and Molecular Dynamics (MD).

Applications of NMR in Drug:Cyclodextrin Complexes.

NMR spectroscopy is an effective technique, applicable for studying bioactive materials or drug delivery systems in order to obtain comprehensive details related to structural and dynamic characteristics at atomic resolution. The applications of NMR spectroscopy have been increased considerably as a result of the combination of advancement in technological NMR instrumentation and scientific knowledge. This chapter is dedicated to highlight the applications of NMR spectroscopy in drug:cyclodextrin complexes using both liquid- and solid-state NMR spectroscopy.

Molecular Dynamics Protocols for the Study of Cyclodextrin Drug Delivery Systems.

Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and eventually to death. A number of marketed medicines consist of active ingredients that may be relatively potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of irbesartan (IRB) as a representative example.

Application of Neutralization and Freeze-Drying Technique for the Preparation of the Beneficial in Drug Delivery 2-Hydroxypropyl-β-Cyclodextrin Complexes with Bioactive Molecules.

Bioavailability of active substances is of great importance for the formulation of a drug product, as it actually reflects drug absorption and achievement of the optimum pharmacological effect. A great number of chemical compounds with excellent pharmacological properties possess low solubility and permeability values, ending in low bioavailability in the human body after administration (especially after per os administration). CDs are oligosaccharides that possess biological properties similar to their linear counterparts, but some of their physicochemical properties differ.

Discovery of a stable tripeptide targeting the N-domain of CRF1 receptor.

The corticotropin-releasing factor (CRF) and its CRF1 receptor (CRFR) play a central role in the maintenance of homeostasis. Malfunctioning of the CRF/CRFR unit is associated with several disorders, such as anxiety and depression. Non-peptide CRFR-selective antagonists have been shown to exert anxiolytic and antidepressant effects on experimental animals.

Antihypertensive activity and molecular interactions of irbesartan in complex with 2-hydroxypropyl-β-cyclodextrin.

Irbesartan (IRB) exerts beneficial effects either alone or in combination with other drugs on numerous diseases, such as cancer, diabetes, and hypertension. However, due to its high lipophilicity, IRB does not possess the optimum pharmacological efficiency. To circumvent this problem, a drug delivery system with 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) was explored.

Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism.

Renin-angiotensin aldosterone system inhibitors are for a long time extensively used for the treatment of cardiovascular and renal diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive drugs by blocking the octapeptide hormone Angiotensin II to stimulate AT1 receptors. The antihypertensive drug candesartan (CAN) is the active metabolite of candesartan cilexetil (Atacand, CC).

Diabetic skin and UV light: Protection by antioxidants.

Non-invasive biophysical methods were used to study the effect of antioxidant gels, which were prepared from Pinus halepensis bark extracts, vitamin C and water, on the skin of diabetic hairless mice irradiated with UV radiation of 1 and 2 minimal erythemal doses (MEDs). The calculated transepidermal water loss (TEWL) for diabetic mice was found to be fivefold higher on day 11 after irradiation, and in all cases, the TEWL values converged to their initial values on day 21. Both pinus and vitamin C gels inhibited the dehydration of the skin, while water gels did not show similar protection.

Discovery of Plant-Origin Natural Product Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

An drug discovery pipeline for the virtual screening of plant-origin natural products (NPs) was developed to explore new direct inhibitors of TNF and its close relative receptor activator of nuclear factor kappa-B ligand (RANKL), both representing attractive therapeutic targets for many chronic inflammatory conditions. Direct TNF inhibition through identification of potent small molecules is a highly desired goal; however, it is often hampered by severe limitations. Our approach yielded a priority list of 15 NPs as potential direct TNF inhibitors that were subsequently tested against TNF and RANKL.

Current Status and Future Prospects of Small-molecule Protein-protein Interaction (PPI) Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

The overexpression of Tumor Necrosis Factor (TNF) is directly related to the development of several autoimmune diseases, such as rheumatoid and psoriatic arthritis, inflammatory bowel disease, Crohn's disease, refractory asthma, and multiple sclerosis. Receptor Activator of Nuclear Factor Kappa- B Ligand (RANKL) belongs to the TNF family and is the primary mediator of osteoclast-induced bone resorption through interaction with its receptor RANK. The function of RANKL is physiologically inhibited by the action of osteoprotegerin (OPG), which is a decoy receptor that binds to RANKL and prevents the process of osteoclastogenesis.

Topical Treatment of Skin Injury Inflicted in Mice by X-Ray Irradiation.

Background/aims: There is no treatment, without side effects, efficiently preventing or curing skin burns, caused by radiotherapy. A new experimental topical treatment protocol was assessed in mice receiving orthovoltage X-rays at an equivalent dose to that applied to human breast cancer patients in conventional radiotherapy.

Methods: SKH-HR2 female hairless mice were irradiated on their dorsum with a total dose of 4,300 cGy during a 1-month period (20 fractions).

Consensus Predictive Model for Human K562 Cell Growth Inhibition through Enalos Cloud Platform.

β-Thalassemia is an inherited hematologic disorder caused by various mutations of the β-globin gene, thus resulting in a significant decrease in adult hemoglobin (HbA) production. An increase in fetal hemoglobin (HbF) levels by drug molecules is considered of great potential in β-thalassemia treatment and is expected to counterbalance the impaired production of HbA. In this work, based on a set of 129 experimentally tested biological inhibitors, we developed and validated a computational model for the prediction of K562 functional inhibition, possibly associated with HbF induction.

Computational investigation of fullerene-DNA interactions: Implications of fullerene's size and functionalization on DNA structure and binding energetics.

DNA is the building block of life, as it carries the biological information controlling development, function and reproduction of all organisms. However, its central role in storing and transferring genetic information can be severely hindered by molecules with structure altering abilities. Fullerenes are nanoparticles that find a broad spectrum of uses, but their toxicological effects on living organisms upon exposure remain unclear.

Cheminformatics-aided discovery of small-molecule Protein-Protein Interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL).

We present an in silico drug discovery pipeline developed and applied for the identification and virtual screening of small-molecule Protein-Protein Interaction (PPI) compounds that act as dual inhibitors of TNF and RANKL through the trimerization interface. The cheminformatics part of the pipeline was developed by combining structure-based with ligand-based modeling using the largest available set of known TNF inhibitors in the literature (2481 small molecules). To facilitate virtual screening, the consensus predictive model was made freely available at: http://enalos.

Compilation of Data and Modelling of Nanoparticle Interactions and Toxicity in the NanoPUZZLES Project.

The particular properties of nanomaterials have led to their rapidly increasing use in diverse fields of application. However, safety assessment is not keeping pace and there are still gaps in the understanding of their hazards. Computational models predicting nanotoxicity, such as (quantitative) structure-activity relationships ((Q)SARs), can contribute to safety evaluation, in line with general efforts to apply alternative methods in chemical risk assessment.

Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches.

A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson-Boltzmann surface area free-energy calculations for the five ligand-HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50'), as well as interactions with residues of the active site (Asp25/25'/29/29'/30/30').

Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations.

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described.

A Comprehensive Computational Study of the Interaction between Human Serum Albumin and Fullerenes.

Human serum albumin (HSA) is the most abundant blood plasma protein, which transports fatty acids, hormones, and drugs. We consider nanoparticle-HSA interactions by investigating the binding of HSA with three fullerene analogs. Long MD simulations, quantum mechanical (fragment molecular orbital, energy decomposition analysis, atoms-in-molecules), and free energy methods elucidated the binding mechanism in these complexes.

Elucidation of the binding mechanism of renin using a wide array of computational techniques and biological assays.

We investigate the binding mechanism in renin complexes, involving three drugs (remikiren, zankiren and enalkiren) and one lead compound, which was selected after screening the ZINC database. For this purpose, we used ab initio methods (the effective fragment potential, the variational perturbation theory, the energy decomposition analysis, the atoms-in-molecules), docking, molecular dynamics, and the MM-PBSA method. A biological assay for the lead compound has been performed to validate the theoretical findings.

Biological and computational evaluation of resveratrol inhibitors against Alzheimer's disease.

It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis.

Investigation of the interactions of silibinin with 2-hydroxypropyl-β-cyclodextrin through biophysical techniques and computational methods.

Cyclodextrins (CDs) are a well-known class of supermolecules that have been widely used to protect drugs against conjugation and metabolic inactivation as well as to enhance the aqueous solubility and hence to ameliorate the oral bioavailability of sparingly soluble drug molecules. The hepatoprotectant drug silibinin can be incorporated into CDs, and here we elucidate the interaction between the drug and the host at the molecular level. The complexation product of silibinin with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is characterized by Differential Scanning Calorimetry, mass spectrometry, solid and liquid high-resolution NMR spectroscopy.

Stability and binding effects of silver(I) complexes at lipoxygenase-1.

An anti-inflammatory complex of Ag(I), namely [Ag(tpp)3(asp)](dmf) [tpp = triphenylphosphine, aspH = aspirin, dmf = N,N-dimethylformamide], was synthesized in an attempt to develop novel metallotherapeutic molecules. STD (1)H NMR experiments were used to examine if this complex binds to LOX-1. The (1)H NMR spectra in buffer Tris/D2O betrayed the existence of two complexes: the complex of aspirin and the complex of salicylic acid produced after deacetylation of aspirin.

Elucidation of conformational states, dynamics, and mechanism of binding in human κ-opioid receptor complexes.

Opioid G protein-coupled receptors (GPCRs) have been implicated in modulating pain, addiction, psychotomimesis, mood and memory, among other functions. We have employed the recently reported crystal structure of the human κ-opioid receptor (κ-OR) and performed molecular dynamics (MD), free energy, and ab initio calculations to elucidate the binding mechanism in complexes with antagonist JDTic and agonist SalA. The two systems were modeled in water and in DPPC lipid bilayers, in order to investigate the effect of the membrane upon conformational dynamics.

Systematic molecular dynamics, MM-PBSA, and ab initio approaches to the saquinavir resistance mechanism in HIV-1 PR due to 11 double and multiple mutations.

Mutations in the human immunodeficiency virus (HIV) enable virus replication even when appropriate antiretroviral therapy is followed, thus leading to the emergence of drug resistance. In a previous work, we systematically examined seven single mutations that are associated with saquinavir (SQV) resistance in HIV-1 protease (Tzoupis, H.; Leonis, G.