Ligand Conformation Dictates Membrane and Endosomal Trafficking of Arginine‐Glycine‐Aspartate (RGD)‐Functionalized Mesoporous Silica Nanoparticles

Recent breakthrough research on mesoporous silica nanoparticle (MSN) materials has illustrated their significant potential in biological applications due to their excellent drug delivery and endocytotic behavior. We set out to determine if MSN, covalently functionalized with conformation specific bioactive molecules (either linear or cyclic RGD ligands), behave towards mammalian cells in a similar manner as the free ligands. We discovered that RGD immobilized on the MSN surface did not influence the integrity of the porous matrix and improved the endocytosis efficiency of the MSN materials. Through competition experiments with free RGD ligands, we also discovered a conformation specific receptor–integrin association. The interaction between RGD immobilized on the MSN surface and integrins plays an important role in endosome trafficking, specifically dictating the kinetics of endosomal escape. Thus, covalent functionalization of biomolecules on MSN assists in the design of a system for controlling the interface with cancer cells.     

咳嗽变异性哮喘患儿白三烯水平与白三烯受体拮抗剂疗效的相关研究

目的探讨不同白三烯（LT）水平的咳嗽变异性哮喘（CVA）患儿接受白三烯受体拮抗剂（LTRA）治疗后体内LT水平变化与临床疗效的关系。方法以本地300例同年龄儿童所测定的尿LTE4值（25.17±14.26）ng/L作为基础对照,将使用LTRA孟鲁司特治疗的67例CVA患儿按LTE4水平是否高于基础对照水平的2SD,分成LTRA-高（H）组25例和LTRA-低（L）组42例,治疗1个月后观察尿LTE4水平变化和临床疗效;采用相同方法将使用吸入糖皮质激素（ICS）氟替卡松治疗的60例患儿分成ICS-H组20例和ICS-L组40例进行对照。结果所有CVA患儿尿LTE4水平与基础对照相比均有统计学差异（均P＜0.05）;在接受2种不同方法治疗1个月后,LTRA-H组、LTRA-L组和ICS-H组患儿尿LTE4水平均有明显下降（均P＜0.05）,但ICS-L组无明显变化（P＞0.05）。LTRA组与ICS组总体疗效相当（P＞0.05）;LTRA-H组疗效优于LTRA-L组（P＜0.05）,LTRA-L组与ICS-H组、ICS-L组疗效均无统计学差异（均P＞0.05）。结论 CVA患儿采用LTRA和ICS治疗总体疗效相当;体内LT水平与LTRA临床疗效密切相关,LT水平高者疗效优于低者;尿LTE4检测可以作为临床选用LTRA的指标。     

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

Toll-like receptor 7 (TLR7) is activated in response to the binding of single-stranded RNA. Its over-activation has been implicated in several autoimmune disorders, and thus, it is an established therapeutic target in such circumstances. TLR7 small-molecule antagonists are not yet available for therapeutic use. We conducted a ligand-based drug design of new TLR7 antagonists through a concerted effort encompassing 2D-QSAR, 3D-QSAR, and pharmacophore modelling of 54 reported TLR7 antagonists. The developed 2D-QSAR model depicted an excellent correlation coefficient (R²_training: 0.86 and R²_test: 0.78) between the experimental and estimated activities. The ligand-based drug design approach utilizing the 3D-QSAR model (R²_training: 0.95 and R²_test: 0.84) demonstrated a significant contribution of electrostatic potential and steric fields towards the TLR7 antagonism. This consolidated approach, along with a pharmacophore model with high correlation (R_training: 0.94 and R_test: 0.92), was used to design quinazoline-core-based hTLR7 antagonists. Subsequently, the newly designed molecules were subjected to molecular docking onto the previously proposed binding model and a molecular dynamics study for a better understanding of their binding pattern. The toxicity profiles and drug-likeness characteristics of the designed compounds were evaluated with in silico ADMET predictions. This ligand-based study contributes towards a better understanding of lead optimization and the future development of potent TLR7 antagonists.     

Is the Antidepressant Activity of Selective Serotonin Reuptake Inhibitors Mediated by Nicotinic Acetylcholine Receptors?

It is generally assumed that selective serotonin reuptake inhibitors (SSRIs) induce antidepressant activity by inhibiting serotonin (5-HT) reuptake transporters, thus elevating synaptic 5-HT levels and, finally, ameliorates depression symptoms. New evidence indicates that SSRIs may also modulate other neurotransmitter systems by inhibiting neuronal nicotinic acetylcholine receptors (nAChRs), which are recognized as important in mood regulation. There is a clear and strong association between major depression and smoking, where depressed patients smoke twice as much as the normal population. However, SSRIs are not efficient for smoking cessation therapy. In patients with major depressive disorder, there is a lower availability of functional nAChRs, although their amount is not altered, which is possibly caused by higher endogenous ACh levels, which consequently induce nAChR desensitization. Other neurotransmitter systems have also emerged as possible targets for SSRIs. Studies on dorsal raphe nucleus serotoninergic neurons support the concept that SSRI-induced nAChR inhibition decreases the glutamatergic hyperstimulation observed in stress conditions, which compensates the excessive 5-HT overflow in these neurons and, consequently, ameliorates depression symptoms. At the molecular level, SSRIs inhibit different nAChR subtypes by noncompetitive mechanisms, including ion channel blockade and induction of receptor desensitization, whereas α9α10 nAChRs, which are peripherally expressed and not directly involved in depression, are inhibited by competitive mechanisms. According to the functional and structural results, SSRIs bind within the nAChR ion channel at high-affinity sites that are spread out between serine and valine rings. In conclusion, SSRI-induced inhibition of a variety of nAChRs expressed in different neurotransmitter systems widens the complexity by which these antidepressants may act clinically.     

Comparative molecular field analysis of CCK-A antagonists using field-fit as an alignment technique. A convenient guide to design new CCK-A ligands

Summary Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate the affinities of several antagonists towards CCK-A receptors with their steric and electrostatic fields. In this publication, we describe, for the first time, a field-fit operation as an alignment technique. These results could serve as a guide for the design of new non-peptide antagonists.     

A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists

Summary Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods to identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to 13 diverse sets of compounds showing different levels of biological activity. A systematic conformational analysis was carried out to obtain sterically accessible conformations for these flexible compounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimized AM1) from each compound's data set that best fits the biophoric pattern and the resulting superimposition with all the other data-set compounds. Apex-3D identified three common biophoric features important for activity: one as the hydroxyl, acetyl, carbonyl and carboxyl groups, which mimic the acid-binding region of an agonist, the other as the hydrogen-bond donating site, and the third part is represented by a plane in which lipophilic aromatic groups align. The structure-activity relationships were then assessed by using the 3D-QSAR model. A common biophore model is proposed from the Apex-3D analysis which may be useful in designing new pLT antagonists. Molecular volumes and electrostatic potential similarities were also calculated in order to obtain the important structural requirements for the activity.