7 research outputs found
Discovery of Potential KRAS-SOS1 Inhibitors from South African Natural Compounds: An In silico Approach
No full textFor decades the direct targeting of KRAS as a driver of non small cell lung cancer, colorectal and pancreatic cancers as well as the inhibition of the RAF-MEK-ERK pathway has shown little success due to feedback networks that keep the pathway in control. Inhibiting SOS1, a KRAS activator, has therefore become a promising escape route to treating KRAS-driven cancers. The search for SOS1 inhibitors has since gained momentum although no drug has been approved yet. Owing to the time-consuming and difficult processes that characterize the discovery and approval of drugs, natural products have become useful in addressing the unmet medical needs. In this study we employed computational techniques to screen South African natural products for inhibitors with the potential to inhibit SOS1-KRAS activation. In this study, eight natural compounds, from plants and marine life, possessing antineoplastic activities with good docking and ADMET properties were identified. These compounds, viz., SANCDB00219, SANCDB0290, SANCDB00369, SANCDB00416, SANCDB00421, SANCDB00749, SANCDB00957 and SANCDB001124 exhibited
favorable total free binding energies in complex with SOS1-KRAScharacterized by conventional and carbon hydrogen bonds, van der Waals, pi-alkyl and pi-sigma interactions with the binding site residues. It was further revealed that these compounds induced conformational stability on the structural architecture of SOS1-KRAS, and decreased the structural flexibility of its individual C-α atoms as a mechanism of inhibition. Upon experimental validation, these compounds from a natural origin could serve as lead identification of small molecules to address SOS1-KRAS associated diseases
Design, synthesis, biological and computational screening of novel pyridine-based thiadiazole derivatives as prospective anti-inflammatory agents
No full textIn this study, a novel series of pyridine-based thiadiazole derivatives (NTD1-NTD5) were synthesized as prospective anti-inflammatory agents by combining substituted carboxylic acid derivatives of 5-substituted-2-amino-1,3,4-thiadiazole with nicotinoyl isothiocyanate in the presence of acetone. The newly synthesized compounds were characterized by FTIR, 1H NMR, 13C NMR, and mass spectrometry. First, the compounds underwent rigorous in vivo testing for acute toxicity and anti-inflammatory activity and the results revealed that three compounds-NTD1, NTD2, and NTD3, displayed no acute toxicity and significant anti-inflammatory activity, surpassing the efficacy of the standard drug, diclofenac. Notably, NTD3, which featured benzoic acid substitution, emerged as the most potent anti-inflammatory agent among the screened compounds. To further validate these findings, an in silico docking study was carried out against COX-2 bound to diclofenac (PDB ID: 1pxx). The computational analysis demonstrated that NTD2, and NTD3, exhibited substantial binding affinity, with the lowest binding energies (−8.5 and −8.4, kcal/mol) compared to diclofenac (−8.4 kcal/mol). This alignment between in vivo and in silico data supported the robust anti-inflammatory potential of these derivatives. Moreover, molecular dynamics simulations were conducted, extending over 100 ns, to examine the dynamic interactions between the ligands and the target protein. The results solidified NTD3's position as a leading candidate, showing potent inhibitory activity through strong and sustained interactions, including stable hydrogen bond formations. This was further confirmed by RMSD values of 2-2.5 Å and 2-3Ǻ, reinforcing NTD3's potential as a useful anti-inflammatory agent. The drug likeness analysis of NTD3 through SwissADME indicated that most of the predicted parameters including Lipinski rule were within acceptable limits. While these findings are promising, further research is necessary to elucidate the precise relationships between the chemical structures and their activity, as well as to understand the mechanisms underlying their pharmacological effects. This study lays the foundation for the development of novel anti-inflammatory therapeutics, potentially offering improved efficacy and safety profiles
In vitro antimitotic activity and in silico study of some 6-fluoro-triazolo-benzothiazole analogues
No full textIn this work, nine 6-fluoro-triazolo-benzothiazole derivatives were prepared and evaluated for in vitro antimitotic activity. In addition, in silico study was also done using tubulin protein (PDB: 6QQN) by molecular docking method. Results revealed that TZ2 and TZ9 were the most active compounds with antimitotic action opposing the standard drug, aspirin. Results of molecular docking exhibited the inhibitory potential of triazolo-benzothiazole against tubulin protein. The mitotic study indicates the efficacy of triazolo-benzothiazole analogues in inhibiting the proliferation of cancer cells either by promoting microtubule formation or affecting microtubules, thereby preventing microtubule breakdown
Longitudinal Renal Function in Liver Transplant Recipients With Acute-on-Chronic Liver Failure
No full textAssociation between longer hospitalization and development of de novo donor specific antibodies in simultaneous liver–kidney transplant recipients
No full text© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Background:De novo Donor Specific Antibodies (DSA) are considered as a risk factor for the kidney allograft outcomes in recipients after simultaneous liver–kidney transplantation (SLKT). We hypothesized that length of hospital stay (LOS) might be associated with de novo DSA development of due to the increased likelihood of receiving blood transfusions with reduced immunosuppressive regimens. Methods: This study is a single-center, retrospective cohort study consisting of 85 recipients who underwent SLKT from 2009 to 2018 in our hospital. We divided the patients into two groups according to LOS [long hospital stay (L) group (LOS \u3e14 days) and short hospital stay (S) group (LOS ≤14 days)]. Propensity score (PS) has been created using logistic regression to predict LOS greater than median of 14 days. The association between the presence of de novo DSA and LOS was assessed by logistic regression models adjusted for PS. Results: The mean age at transplantation of the entire cohort was 55.5 ± 10.1 years. Sixty percent of the recipients were male and Caucasian. Median LOS in (L) group was three-fold longer than (S) group [L: median 30 days (IQR: 21–52), S: median 8.5 days (IQR: 7–11)]. Eight patients developed de novo DSA after SLKT (9.4%), all of them were in (L) group. Longer LOS was significantly associated with higher risk of development of de novo DSA in unadjusted (OR+ each 5 days: 1.09, 95% CI:1.02–1.16) and PS adjusted (OR+ each 5 days: 1.11, 95% CI:1.02–1.21) analysis. Conclusion: Longer hospitalization is significantly associated with the development of de novo DSA in SLKT
The transcriptome of Populus in elevated CO2 reveals increased anthocyanin biosynthesis during delayed autumnal senescence
No full textThe delay in autumnal senescence that has occurred in recent decades has been linked to rising temperatures. Here, we suggest that increasing atmospheric CO2 may partly account for delayed autumnal senescence and for the first time, through transcriptome analysis, identify gene expression changes associated with this delay.Using a plantation of Populus × euramericana grown in elevated [CO2] (e[CO2]) with free-air CO2 enrichment (FACE) technology, we investigated the molecular and biochemical basis of this response. A Populus cDNA microarray was used to identify genes representing multiple biochemical pathways influenced by e[CO2] during senescence. Gene expression changes were confirmed through real-time quantitative PCR, and leaf biochemical assays.Pathways for secondary metabolism and glycolysis were significantly up-regulated by e[CO2] during senescence, in particular, those related to anthocyanin biosynthesis. Expressed sequence tags (ESTs) representing the two most significantly up-regulated transcripts in e[CO2], LDOX (leucoanthocyanidin dioxgenase) and DFR (dihydroflavonol reductase), gave (e[CO2]/ambient CO2 (a[CO2])) expression ratios of 39.6 and 19.3, respectively.We showed that in e[CO2] there was increased autumnal leaf sugar accumulation and up-regulation of genes determining anthocyanin biosynthesis which, we propose, prolongs leaf longevity during natural autumnal senescence.<br/
Directed self-assembly of quantum structures by nanomechanical stamping using probe tips
No full textWe demonstrate that nanomechanically stamped substrates can be used as templates to pattern and direct the self-assembly of epitaxial quantum structures such as quantum dots. Diamond probe tips are used to indent or stamp the surface of GaAs( 100) to create nanoscale volumes of dislocation-mediated deformation, which alter the growth surface strain. These strained sites act to bias nucleation, hence allowing for selective growth of InAs quantum dots. Patterns of quantum dots are observed to form above the underlying nanostamped template. The strain state of the patterned structures is characterized by micro-Raman spectroscopy. The potential of using nanoprobe tips as a quantum dot nanofabrication technology are discussed
