Latest research shows that SERPINE1 overexpression has an important role in Coronavirus 2019 (COVID-19)-associated coagulopathy leading to acute respiratory distress syndrome (ARDS). However, ways to ...target this protein remain elusive. In this forum, we discuss recent evidence linking SERPINE1 with COVID-19-related ARDS and summarize the available data on inhibitors of this target.
The angiotensin II (Ang II) type 1 and type 2 receptors (AT1R and AT2R) orchestrate an array of biological processes that regulate human health. Aberrant function of these receptors triggers ...pathophysiological responses that can ultimately lead to death. Therefore, it is important to design and synthesize compounds that affect beneficially these two receptors. Cardiovascular disease, which is attributed to the overactivation of the vasoactive peptide hormone Αng II, can now be treated with commercial AT1R antagonists. Herein, recent achievements in rational drug design and synthesis of molecules acting on the two AT receptors are reviewed. Quantitative structure activity relationships (QSAR) and molecular modeling on the two receptors aim to assist the search for new active compounds. As AT1R and AT2R are GPCRs and drug action is localized in the transmembrane region the role of membrane bilayers is exploited. The future perspectives in this field are outlined. Tremendous progress in the field is expected if the two receptors are crystallized, as this will assist the structure based screening of the chemical space and lead to new potent therapeutic agents in cardiovascular and other diseases.
•Targeting serpins with drug-like molecules remains a challenge in drug discovery.•Compounds targeting HSP47, antitrypsin, antithrombin, PAI-1 and neuroserpin are analysed.•The compounds either ...target the physiological role of serpins or their polymerisation.•The mode of action of these compounds is analysed, if known.•Virtual screening and other in silico techniques have been successful in identifying new chemical matter.
Serine protease inhibitors (serpins) are a large family of proteins that regulate and control crucial physiological processes, such as inflammation, coagulation, thrombosis and thrombolysis, and immune responses. The extraordinary impact that these proteins have on numerous crucial pathways makes them an attractive target for drug discovery. In this review, we discuss recent advances in research on small-molecule modulators of serpins, examine their mode of action, analyse the structural data from crystallised protein–ligand complexes, and highlight the potential obstacles and possible therapeutic perspectives. The application of in silico methods for rational drug discovery is also summarised. In addition, we stress the need for continued research in this field.
The discovery of drug-like chemical matter targeting proteins with multiple conformational states, such as serpins, remains a challenge in drug discovery. This review examines recent advances in serpin therapeutic design.
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Natural products have served as a rich source for drug discovery and development. In the last decade their fruitful integration in the drug discovery pipeline declined due to their ...reduced bioavailability, mainly attributed to their poor aqueous solubility. We synthesized a quercetin (QUE)⿿(2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) complex that enabled amplification of its solubility and in the same time retained its bioactivity in T24 human bladder cancer cell line. The stability of the complex and the molecular basis of the interactions developed in this host-guest complex were assayed by incorporating an array of analytical techniques and Molecular Dynamics (MD) experiments. 2D DOSY NMR experiment revealed that the diffusion coefficient of free HP-β-CD was 3.55ÿ10⿿10m2s⿿1 while that of QUE⿿HP-β-CD inclusion complex 3.09ÿ10⿿10m2s⿿1, indicating the formation of a complex. Solid and liquid high resolution NMR spectroscopy data showed that the most pronounced differences in chemical shifts at carbons and protons correspondingly during complexation occur in the aromatic ring ο (bearing the two phenolic hydroxyl groups meta to each other). The chemical shift differences in the aromatic ring ο (bearing the two phenolic hydroxyl groups ortho to each other) were less pronounced. The MD results confirmed the experimental data.
Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL), may affect plasma HDL-cholesterol levels and cardiovascular risk. ...Here, we evaluated the effect of human apoA-I mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an effort to explain the phenotypes of subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations, with apoA-IL178P presenting the greatest thermodynamic destabilization. Additionally, apoA-IL178P displayed reduced ABCA1-mediated cholesterol efflux capacity. When in reconstituted HDL (rHDL), apoA-IL144R and apoA-IL178P were more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol efflux capacity and apoA-IL144R showed severe LCAT activation defect. ApoA-IA164S was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Specifically, it had reduced ABCG1-mediated cholesterol and 7-ketocholesterol efflux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-IA164S to activate Akt kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-IA164S to preserve endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure–function analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations.
The angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this ...critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational analysis results obtained using a combination of NMR spectroscopy and Molecular Modeling. The same AT1R antagonists are docked and compared in terms of their interactions in their binding site using homology models and the crystallized AT1R receptor. Various aspects derived from these comparisons regarding rational drug design are outlined.
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•Rosemary tea is characterized by the presence of diterpenes, flavonoids and hydroxycinnamic derivatives.•Regular consumption of rosemary infusion causes anxiolytic-like behavior in ...mice.•Regular consumption of rosemary infusion causes antidepressant-like behavior in mice.•Regular consumption of rosemary tea decreases cerebral and hepatic ChE activity.•Rosemary compounds have common chemical features with known AChE drug inhibitors.
Our aim was to investigate the possible effects of regular drinking of Rosmarinus officinalis L. leaf infusion on behavior and on AChE activity of mice. Rosemary tea (2% w/w) phytochemical profile was investigated through LC/DAD/ESI-MSn. Adult male mice were randomly divided into two groups: “Rosemary-treated” that received orally the rosemary tea for 4weeks and “control” that received drinking water. The effects of regular drinking of rosemary tea on behavioral parameters were assessed by passive avoidance, elevated plus maze and forced swimming tests. Moreover, its effects on cerebral and liver cholinesterase (ChE) isoforms activity were examined colorimetricaly. Phytochemical analysis revealed the presence of diterpenes, flavonoids and hydroxycinnamic derivatives in rosemary tea; the major compounds were quantitatively determined. Its consumption rigorously affected anxiety/fear and depression-like behavior of mice, though memory/learning was unaffected. ChE isoforms activity was significantly decreased in brain and liver of “rosemary treated” mice. In order to explain the tissue ChE inhibition, principal component analysis, pharmacophore alignment and molecular docking were used to explore a possible relationship between main identified compounds of rosemary tea, i.e. rosmarinic acid, luteolin-7-O-glucuronide, caffeic acid and known AChE inhibitors. Results revealed potential common pharmacophores of the phenolic components with the inhibitors. Our findings suggest that rosemary tea administration exerts anxiolytic and antidepressant effects on mice and inhibits ChE activity; its main phytochemicals may function in a similar way as inhibitors.
Introduction: New drug formulations against hypertension have a vital role in the quality of human life, as this risk factor for cardiovascular disease can be life threatening. A modern life style ...characterized by less exercise, smoking, drinking and poor diet has increased the risk of developing hypertension, the so-called silent killer, in civilized communities and thus an urgent defense is needed against this enemy.
Areas covered: In this review, the authors provide extensive information on pharmaceutical formulations containing anti-hypertensive drugs, as well as on general and specific patents. Thus, readers can understand the advances and new trends in the field.
Expert opinion: A considerable effort has been made to provide new and improved formulations, comprising anti-hypertensive drugs with new excipients, appropriate particle size, containing alkaline salts or included in cyclodextrins in an attempt to avoid known existing problems. New types of formulations are expected to emerge in the near future that will allow for more effective and spatiotemporally controlled drug delivery, which will be better tolerated by the patients and will provide better pharmaceutical treatment. Such an example is the new cocktail formulations that contain more than one active component, act synergistically and therefore have optimized pharmacological benefits. Formulations using multitarget antihypertensive drugs are also expected to be commercially available in the near future.
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. The chemical shift changes using 13C CP/MAS on the complexing of the guest with the host provided significant information on the molecular interactions, and they were in agreement with the 2D NOESY results. These results point out that in both solid and liquid forms, the drug is engulfed and interacts with HP-β-CD in identical manner. Molecular dynamics calculations have been performed to examine the thermodynamic characteristics associated with the silibinin–HP-β-CD interactions and to study the stability of the complex. To approximate the physiological conditions, the aqueous solubility and dissolution characteristics of the complex at pH states simulating those of the upper gastrointestinal tract have been applied. To evaluate the antiproliferative activity of silibinin–HP-β-CD complex comparatively to silibinin in MCF-7 human cancer cells, MTT assays have been performed.
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