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In the present investigation, a novel thermophilic L-asparaginase (Asn_PA) from Pseudomonas aeruginosa CSPS4 was investigated to explore its structural insights at elevated temperatures. Sequence analysis of Asn_PA depicted three conserved motifs (VVILATGGTIAG, DGIVITHGTDTLEETAYFL, and, LRKQGVQIIRSSHVNAGGF), of them, two motifs exhibit catalytically-important residues i.e., T45 and T125. A homology modelling-based structure model for Asn_PA was generated with 4PGA as the top-matched template. The predicted structure was validated and energy was minimized. Molecular docking was carried out cantered at the active site for asparagine and glutamine as its substrate ligands. The enzyme–substrate interaction analysis showed binding affinities of – 4.8 and – 4.1 kcal/mol for asparagine and glutamine respectively. Molecular dynamics (MD) simulation studies showed a better stability of Asn_PA at temperatures of 60 °C, over 40, 50 and, 80 °C, making this enzyme a novel L-asparaginase from other mesophilic P. aeruginosa strain. The trajectory analysis showed that RMSD, Rg, and, SASA values correlate well with each other in the different tested temperatures during the MD analysis. Thus, the present findings encourage extensive characterization of the Asn_PA using laboratory experiments to understand the structural behavior of the active site loop in an open or closed state with and without the substrate molecules. [ABSTRACT FROM AUTHOR]

Energy metabolism is a universal process occurring in all life forms. In Mycobacterium tuberculosis (Mtb) , energy production is carried out in two possible ways, oxidative phosphorylation (OxPhos) and substrate-level phosphorylation. Mtb is an obligate aerobic bacterium, making it dependent on OxPhos for ATP synthesis and growth. Mtb inhabits varied micro-niches during the infection cycle, outside and within the host cells, which alters its primary metabolic pathways during the pathogenesis. In this review, we discuss cellular respiration in the context of the mechanism and structural importance of the proteins and enzyme complexes involved. These protein-protein complexes have been proven to be essential for Mtb virulence as they aid the bacteria's survival during aerobic and hypoxic conditions. ATP synthase, a crucial component of the electron transport chain, has been in the limelight, as a prominent drug target against tuberculosis. Likewise, in this review, we have explored other protein-protein complexes of the OxPhos pathway, their functional essentiality, and their mechanism in Mtb's diverse lifecycle. The review summarises crucial target proteins and reported inhibitors of the electron transport chain pathway of Mtb. [ABSTRACT FROM AUTHOR]

The compounds containing chiral centers and different functional groups serve as magnificent building blocks for the preparation of various natural products that are having immense biological activity. "Dimethyl‐8‐oxa‐bicyclo[3.2.1]oct‐6‐en‐3‐ol" is one of the wonderful synthons to construct multiple stereo centers at a time during the asymmetric synthesis. In this account, we discuss our research efforts toward the synthesis of various simple and complex natural products from the past three decades (1995–2020) by using dimethyl‐8‐oxa‐bicyclo[3.2.1]oct‐6‐en‐3‐ol as a synthon. Moreover, the synthetic utility of this starting material was investigated and well demonstrated. Further, we executed the desymmetrization of dimethyl‐8‐oxa‐bicyclo[3.2.1]oct‐6‐en‐3‐ol by hydroboration to get different chiral centers. After obtaining the stereocenters, we could manage either the fragment, formal or total synthesis of natural products, by simple protection and deprotection sequence followed by C−C bond formation steps. [ABSTRACT FROM AUTHOR]

Kavalactones are classes of α-pyrone and 5,6-dihydropyrone derivatives showing various biological activities, and numerous approaches have been reported for the preparation of these molecules. In this review, we discuss the different synthetic approaches towards these naturally occurring lactones, in both racemic and enantiomerically pure forms, that have been reported in the literature to date. It is hoped that this review will assist researchers in the development of additional and efficient synthetic routes towards kavalactones. 1 Introduction 2 Synthetic Approaches for the Preparation of Kavalactones 3 Conclusion [ABSTRACT FROM AUTHOR]

[Display omitted] In this study, the molecular descriptors (MDs) of a set of halogenated benzooxazepines (BZOs) were evaluated to determine their absorption, distribution, metabolism, excretion, and toxicity properties. Molecular docking and dynamics analyses were performed to investigate the action mechanisms. The optimization of BZOs was carried out using density function theory with Becke's three parameter hybrid functional (B3LYP) at the 6-31G+(d,p) level. Which was further correlated with theoretical and experimental spectroscopic values. Detailed studies were performed on frontier molecular orbitals, quantum chemical descriptors, IR, and NMR spectroscopy. A preliminary structure–activity relationship analysis revealed that BZOs bearing Cl substitution had greater effectiveness, particularly when positioned at the R2-position on the BZO-e system. Further BZOs were used as inhibitors of apoptosis pathway-related protein targets, including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX, apoptotic protease-activating factor 1, poly [ADP-ribose] polymerase 1 (PARP1), and tankyrase 1 for potential anticancer activity. The stability of the receptor-inhibitor complex was validated by the molecular dynamics analysis of the PARP1 complex. [ABSTRACT FROM AUTHOR]

Background: The accumulation of poorly folded protein in the endoplasmic reticulum (ER) promotes ER stress and contributes to the pathogenesis of hepatocellular carcinoma (HCC). Current therapies have various adverse effects, therefore, laying the need for an alternative approach. Kaempferol (KP), a naturally occurring flavonoid, possesses potent anti-proliferative properties against various cancer cells. Nevertheless, its involvement in HCC remains relatively unexplored, particularly regarding its influence on apoptosis and autophagy pathways. Methods: The effect of KP on cell viability, and motility of Hep3B cells was evaluated by MTT, and scratch assay, respectively. Hoechst staining and FACS analysis were done to check the effect of KP on apoptosis and cell cycle progression. qRTPCR was used to evaluate the expression of several apoptosis and autophagy-related genes. KP was docked with several ER stress-related proteins involved in HCC to gain further insights into molecular mechanisms. The results of docking studies were validated with MD simulation and in vitro studies. Results: Treatment with KP at different time intervals showed dose- and time-dependent growth inhibition of liver cancer cells. KP decreased motility and arrested the cell cycle at the G0/G1 phase in Hep3B cells. Additionally, in the context of HCC, the relationship between KP, apoptosis, and autophagy is significant. It induced apoptosis and autophagy in Hep3B cells by downregulating the expression of Bcl-2 and upregulated Bax and Bid, Caspase-3, Beclin-1, and LC3. KP showed a better binding affinity with Nrf2, PERK, and IRE1α among all selected proteins. Further, it reversed the protective effect of 4-PBA (ER Stress inhibitor) by inducing apoptosis and autophagy in Hep3B cells. Conclusion: The study suggested KP as a potential chemopreventive agent for managing HCC by effectively inducing apoptosis and autophagy in Hep3B cells. [ABSTRACT FROM AUTHOR]

• Apoptosis pathway related proteins are attractive target against cancers. • Various molecular and quantum chemical descriptors used to denote different molecular properties. • Indole-fused benzooxazepines derivatives were analyzed to characterize their ability as anti-cancer drugs. • IFBO-7 showed top binding mode as -15.7 kJ/mol and the dissociation constant (K d) 6.1 µM against PARP1. • -OCH 3 and -OH substitutions over the indole-fused benzooxazepines enhance their binding affinity. In this study, quantum chemical (QC) investigations, virtual screening, molecular docking, and molecular dynamics analysis of indole-fused benzooxazepines derivatives (IFBOs) are presented. The ab-initio density function theory (DFT) using Becke's three parameters hybrid functional (B3LYP) and Hartree-Fock (HF) with 6-311+G(d) level of theory were used to optimize IFBOs. The most suitable level is determined as DFT(B3LYP)6-311+G(d) by correlation of observed and calculated results of IFBOs (1-8). IR, NMR, quantum chemical descriptors, and frontier molecular orbitals (FMOs) were examined in detail. Similarly, virtual drug-likeness screening of IFBOs (1-8) was also performed including molecular descriptors (MDs) and bioactivity score (BS) along with absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were computed to reveal their biological activity. Moreover, their potential anticancer activity target was explored by molecular docking and molecular dynamics analyses. Mainly apoptosis pathway-related protein targets including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX and poly-ADP-ribose-polymerase-1 (PARP1) were studied to find the most prominent target of IFBOs to display their potential anticancer activity. As a result, IFBO-7 revealed the best molecular interaction profile with PARP1 and showed its potent inhibitory activity. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: This paper investigates the uncertain maximum flow of a network whose capacities are random fuzzy variables. We have developed the expected value model (EVM) and the chance‐constrained model (CCM) for maximum flow problem (MFP) under random fuzzy environment and formulated their crisp equivalent models. To solve these models, we have proposed a varying population genetic algorithm with indeterminate crossover (VPGAwIC). In VPGAwIC, selection of a chromosome depends on its lifetime. An improved lifetime allocation strategy (iLAS) has also been proposed to determine the lifetime of the chromosome. The ages of the chromosomes are defined linguistically as  Young, Middle, and Old, which follow some uncertainty distributions. The crossover probability is indeterminate, and it depends on the ages of the parents, which is defined by an uncertain rule base. The number of offspring, generated from a population of parents, is determined by the reproduction ratio. The population is updated in 2 ways: (i) All the chromosomes with ages greater than their lifetimes are discarded from the population, and (ii) the offspring are combined with their parents for the next generation. The proposed VPGAwIC is compared with the genetic algorithm developed by Gen, Cheng, and Lin (2008) for maximum flow problem. Wilcoxon signed‐rank test has been performed to show the superiority of the proposed VPGAwIC. [ABSTRACT FROM AUTHOR]