Study of andrographolide bioactivity against Pseudomonas aeruginosa based on computational methodology and biochemical analysis

Andrographolide is one of the main biologically active molecules isolated from Andrographis paniculata (A. paniculata), which is a traditional Chinese herb used extensively throughout Eastern Asia, India, and China. Pseudomonas aeruginosa, often known as P. aeruginosa, is a common clinical opportunistic pathogen with remarkable adaptability to harsh settings and resistance to antibiotics. P. aeruginosa possesses a wide array of virulence traits, one of which is biofilm formation, which contributes to its pathogenicity. One of the main modulators of the P. aeruginosa-controlled intramembrane proteolysis pathway is AlgW, a membrane-bound periplasmic serine protease. In this work, we have used a set of density functional theory (DFT) calculations to understand the variety of chemical parameters in detail between andrographolide and levofloxacin, which show strong bactericidal activity against P. aeruginosa. Additionally, the stability and interaction of andrographolide and levofloxacin with the protein AlgW have been investigated by molecular docking and molecular dynamics (MD) simulations . Moreover, the growth and inhibition of biofilm production by P. aeruginosa experiments were also investigated, providing insight that andrographolide could be a potential natural product to inhibit P. aeruginosa

Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

20(S)-Sulfonylamidine CPT-derivatives were prepared and tested for cytotoxicity.Several analogs showed superior cytotoxic activity compared to irinotecan.Key structural features related to cytotoxicity were identified by SAR analysis.Compounds 9 and 15c interacted with Topo I-DNA by a different binding mode from CPT.These compounds are new generation CPT-derived antitumor agents.In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I

Phytoremediation Potential of Three Species of Macrophytes for Nitrate in Contaminated Water

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Sivelestat sodium attenuates acute lung injury by inhibiting JNK/NF-κB and activating Nrf2/HO-1 signaling pathways

Sivelestat sodium (SIV), a neutrophil elastase inhibitor, is mainly used for the clinical treatment of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). However, studies investigating the effects of SIV treatment of ALI are limited. Therefore, this study investigated the potential molecular mechanism of the protective effects of SIV against ALI. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with tumor necrosis factor α (TNF-α), and male Sprague-Dawley rats were intratracheally injected with Klebsiella pneumoniae (KP) and treated with SIV, ML385, and anisomycin (ANI) to mimic the pathogenetic process of ALI in vitro and in vivo, respectively. The levels of inflammatory cytokines and indicators of oxidative stress were assessed in vitro and in vivo. The wet/dry (W/D) ratio of lung tissues, histopathological changes, inflammatory cells levels in bronchoalveolar lavage fluid (BALF), and survival rates of rats were analyzed. The JNK/NF-κB (p65) and Nrf2/HO-1 levels in the HPMECs and lung tissues were analyzed by western blot and immunofluorescence analyses. Administration of SIV reduced the inflammatory factors levels, intracellular reactive oxygen species (ROS) production, and malondialdehyde (MDA) levels and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues. Meanwhile, SIV alleviated pathological injuries, decreased the W/D ratio, and inflammatory cell infiltration in lung tissue. In addition, SIV also inhibited the activation of JNK/NF-κB signaling pathway, promoted nuclear translocation of Nrf2, and upregulated the expression of heme oxygenase 1 (HO-1). However, ANI or ML385 significantly reversed these changes. SIV effectively attenuated the inflammatory response and oxidative stress. Its potential molecular mechanism was related to the JNK/NF-κB activation and Nrf2/HO-1 signaling pathway inhibition. This further deepened the understanding of the protective effects of SIV against ALI

Sulfur-Doped BiOCl with Enhanced Light Absorption and Photocatalytic Water Oxidation Activity

Photocatalysis is a powerful strategy to address energy and environmental concerns. Sulfur-doped BiOCl was prepared through a facial hydrothermal method to improve the photocatalytic performance. Experimental results and theoretical calculations demonstrated that the band structure of the sulfur-doped BiOCl was optimally regulated and the light absorption range was expanded. It showed excellent visible-light photocatalytic water oxidation properties with a rate of 141.7 μmol h−1 g−1 (almost 44 times of that of the commercial BiOCl) with Pt as co-catalyst

Ligand Efficiency Outperforms pIC50 both on 2D MLR and 3D CoMFA Models \u2013 A Case Study on AR Antagonists

The concept of ligand efficiency is defined as biological activity in each molecular size and is widely accepted throughout the drug design community. Among different LE indices, surface efficiency index (SEI) was reported to be the best one in support vector machine modeling, much better than the generally and traditionally used end-point pIC50. In this study, 2D multiple linear regression and 3D comparative molecular field analysis methods are employed to investigate the structure-activity relationships of a series of androgen receptor antagonists, using pIC50 and SEI as dependent variables to verify the influence of using different kinds of end-points. The obtained results suggest that SEI outperforms pIC50 on both MLR and CoMFA models with higher stability and predictive ability. After analyzing the characteristics of the two dependent variables SEI and pIC50, we deduce that the superiority of SEI maybe lie in that SEI could reflect the relationship between molecular structures and corresponding bioactivities, in nature, better than pIC50. This study indicates that SEI could be a more rational parameter to be optimized in the drug discovery process than pIC50. We expanded the application of the ligand efficiency SEI to MLR and CoMFA modeling to investigate the relationships between the hydantoin derivatives and AR antagonist activities. The obtained results indicate that the SEI-based models outperform the pIC50-based models with higher stability, robustness, and predictive abilities. We put forward our opinion that SEI can incarnate the relationships between bioactivities and molecular structures better than pIC50, in nature. SEI could be a more rational parameter to be optimized in the drug discovery

Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment 171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model

The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau aggregation. So far, the mechanism of the abnormal acetylation of Tau that affects its misfolding and aggregation is still unclear. Therefore, revealing the effect of acetylation on Tau aggregation could help elucidate the pathogenic mechanism of tauopathies. In this study, molecular dynamics simulation combined with multiple computational analytical methods were performed to reveal the effect of K174 acetylation on the spontaneous aggregation of Tau peptide 171IPAKTPPAPK180, and the dimerization mechanism as an early stage of the spontaneous aggregation was further specifically analyzed by Markov state model (MSM) analysis. The results showed that both the actual acetylation and the mutation mimicking the acetylated state at K174 induced the aggregation of the studied Tau fragment; however, the effect of actual acetylation on the aggregation was more pronounced. In addition, acetylated K174 plays a major contributing role in forming and stabilizing the antiparallel β-sheet dimer by forming several hydrogen bonds and side chain van der Waals interactions with residues I171, P172, A173 and T175 of the corresponding chain. In brief, this study uncovered the underlying mechanism of Tau peptide aggregation in response to the lysine K174 acetylation, which can deepen our understanding on the pathogenesis of tauopathies

Molecular Modeling Study on the Allosteric Inhibition Mechanism of HIV-1 Integrase by LEDGF/p75 Binding Site Inhibitors

<div><p>HIV-1 integrase (IN) is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD) with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger <i>tert</i>-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.</p></div

Binding Thermodynamics and Dissociation Kinetics Analysis Uncover the Key Structural Motifs of Phenoxyphenol Derivatives as the Direct InhA Inhibitors and the Hotspot Residues of InhA

Given the current epidemic of multidrug-resistant tuberculosis, there is an urgent need to develop new drugs to combat drug-resistant tuberculosis. Direct inhibitors of the InhA target do not require activation and thus can overcome drug resistance caused by mutations in drug-activating enzymes. In this work, the binding thermodynamic and kinetic information of InhA to its direct inhibitors, phenoxyphenol derivatives, were explored through multiple computer-aided drug design (CADD) strategies. The results show that the van der Waals interactions were the main driving force for protein&ndash;ligand binding, among which hydrophobic residues such as Tyr158, Phe149, Met199 and Ile202 have high energy contribution. The AHRR pharmacophore model generated by multiple ligands demonstrated that phenoxyphenol derivatives inhibitors can form pi&ndash;pi stacking and hydrophobic interactions with InhA target. In addition, the order of residence time predicted by random acceleration molecular dynamics was consistent with the experimental values. The intermediate states of these inhibitors could form hydrogen bonds and van der Waals interactions with surrounding residues during dissociation. Overall, the binding and dissociation mechanisms at the atomic level obtained in this work can provide important theoretical guidance for the development of InhA direct inhibitors with higher activity and proper residence time