In vitro and in silico exploration of IL-2 inhibition by small drug-like molecules

Interleukin-2 (IL-2) is an immunoregulatory cytokine produced by T lymphocytes in response to antigen. It is a potent growth and differentiation factor for several cell-types and is structurally related to the four-helix bundle family of cytokines. Here, we report IL-2 inhibitory potential and computational studies on different series of chalcones, benzothiazepines, semicarbazones, and dihydropyrimidines. These compounds were synthesized in wet lab and were then tested for their potency as IL-2 inhibitors through in vitro T cell proliferation, IL-2 cytokine production as well as their effect on oxidative burst. Compounds that showed significant suppressive activity were further evaluated for their cytotoxicity on normal two cell lines. Most of the chalcones were found to have a powerful inhibitory effect on T-lymphocytes proliferation and cytokine production. Among the aza heterocycles benzothiazepines, benzoxazepines, and benzodiazepinones were found to be the strongest IL-2 inhibitors. Molecular docking and MD simulation studies were carried out to correlate experimental and theoretical results whereby a good correlation was observed which indicated that computational studies could provide an alternate tool for the identification and designing of more potent IL-2 inhibitors.     

Three-dimensional quantitative structure–activity relationship (CoMSIA) analysis of bis-coumerine analogues as urease inhibitors

As a basis for predicting structural features that may lead to the design of more potent and selective inhibitors of urease, the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out on a series of 30 bis-coumerine analogs, which are known urease inhibitors. Five different properties: steric, electrostatic, hydrophobic, H-bond donor, and H-bond acceptor, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. A significant cross-validated correlation coefficient q2 (0.51), r ² (0.962) for CoMSIA were obtained, indicating the statistical significance of this class of compounds. Actual urease inhibitory activities of this class, and the predicted values were in good agreement with the experimental results. This model offer insight into the structural requirements for activity of bis-coumerine analogues as urease inhibitors, since there is only speculative knowledge of their target in protein.     

Identification of Novel Urease Inhibitors by High-Throughput Virtual and in Vitro Screening

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Molecular docking studies of potent inhibitors of tyrosinase and α-glucosidase

Copper containing tyrosinase enzyme is responsible for melanin biosynthesis in human. Anomalous growth of this enzyme causes hyper-pigmentation related disorders. Melanoma-specific anticarcinogenic activity has also been associated with this enzyme. Recently reported metabolites of tibolone exhibited significant inhibitory activities against both tyrosinase and α-glucosidase enzymes. Molecular docking studies of these enzymes with those metabolites have been the focus of this study. It is comprehensively studied that the inhibition of α-glucosidase is crucial for glycemic control. The active site similarity between tyrosinase and α-glucosidase has also been observed. GOLD is utilized to investigate the conformation and binding affinities of newly discovered inhibitors. In both enzymes, metal ions seem to play an important role in establishing the interaction within the cavity of active sites. Results obtained by recent study are not only consistent with the experimental findings but also provide a deeper insight into the structural attributes and overall molecular interactions.     

Presence of antispasmodic, antidiarrheal, antisecretory, calcium antagonist and acetylcholinesterase inhibitory steroidal alkaloids in Sarcococca saligna

The aim of this investigation was to see if the crude extract of Sarcococca saligna (Ss.Cr) contains chemicals with gut function inhibitory activity by using in vitro and in vivo assays. Ss.Cr caused a dose-dependent (0.03 - 3 mg/mL) inhibitory effect on K+-induced contractions in rat stomach fundus, guinea-pig ileum and rabbit jejunum preparations. The calcium channel blocking(CCB) activity was confirmed when Ss.Cr caused a rightward shift in the Ca++ dose-response curves. It also potentiated, at lower do-ses (0.001 - 0.03 mg/mL), the contractile effect of a fixed dose of acetylcholine (ACh), similar to physostigmine, and suppressed the effect of ACh at higher doses (0.3 - 1.0 mg/mL). Both Ss.Cr and physostigmine inhibited acetylcholinesterase (AChE), in the in vitro assay, confirming the AChE inhibitory activity. In the in vivo studies, Ss.Cr exhibited antidiarrheal and antisecretory activities against castor oil-induced diarrhea and intestinal fluid accumulation in mice. Characteristic steroidal compounds of the plant (saracocine, saracodine, saracorine and alkaloid-C), exhibited a similar combination of AChE inhibitory and CCB activities. Thus this study provides a sound mechanistic base for some of the traditional uses of the plant in hyperactive gut states, in addition to providing the first evidence for verapamil to possess additional AChE inhibitory activity. Furthermore, these characteristic compounds with dual activity may be good candidates for further studies on their usefulness in Alzheimer's disease.     

In silico studies on 2,3-dihydro-1,5-benzothiazepines as cholinesterase inhibitors

In vitro studies on cholinesterase inhibitory potential on the three sets of 2,3-dihydro-1,5-benzothiazepines have been carried out. The compounds in Set 1 were unsubstituted on ring A, while those in Sets 2 and 3 had a 2′- and 3′-hydoxy substituent, respectively, in ring A. These studies revealed that they are mixed inhibitors of both AChE and BChE as reflected from their IC₅₀ values. It was further observed that 3′-hydroxy substituted benzothiazepines (Set 3) were found to have stronger affinity for both AChE and BChE compared with those of Sets 1 and 2. Moreover, all the compounds in Set 3 were found to be stronger BChE inhibitors than AChE. These experimental observations were rationalized by conducting in silico studies using molecular docking tool of Molecular Operating Environment (MOE) software, thereby, a good correlation was observed between IC₅₀ values and their binding interactions within the enzyme active site. We have observed that these interactions were electrostatic and hydrophobic in nature besides hydrogen bonding. The high BChE inhibitory potential of 3′-hydroxy substituted benzothiazepines was found to be cumulative effect of hydrogen bonding and π–π interactions between the ligand and BChE. These findings may serve as a guideline for synthesizing more potent ChE inhibitors for the treatment of Alzheimer’s disease and related dementias.