Understanding Genetic Risks: Computational Exploration of Human ß-Synuclein nsSNPs and their Potential Impact on Structural Alteration.

Synucleins are pivotal in neurodegenerative conditions. Beta-synuclein (ß-synuclein) is part of the synuclein protein family alongside alpha-synuclein (α-synuclein) and gamma-synuclein (γ-synuclein). These proteins, found mainly in brain tissue and cancers, are soluble and unstructured. ß-synuclein shares significant similarity with α-synuclein, especially in their N-terminus, with a 90% match. However, their aggregation tendencies differ significantly. While α-synuclein aggregation is believed to be counteracted by ß-synuclein, which occurs in conditions like Parkinson's disease, ß-synuclein may counteract α-synuclein's toxic effects on the nervous system, offering potential treatment for neurodegenerative diseases. Under normal circumstances, ß-synuclein may guard against disease by interacting with α-synuclein. Yet, in pathological environments with heightened levels or toxic substances, it might contribute to disease. Our research aims to explore potential harmful mutations in the ß-synuclein using computational tools to predict their destabilizing impact on protein structure. Consensus analysis revealed rs1207608813 (A63P), rs1340051870 (S72F), and rs1581178262 (G36C) as deleterious. These findings highlight the intricate relationship between nsSNPs and protein function, shedding light on their potential implications in disease pathways. Understanding the structural consequences of nsSNPs is crucial for elucidating their role in pathogenesis and developing targeted therapeutic interventions. Our results offer a robust computational framework for identifying neurodegenerative disorder-related mutations from SNP datasets, potentially reducing the costs associated with experimental characterization.

Plasmodium falciparum Malaria Presenting as a Thrombotic Thrombocytopenic Purpura (TTP) Mimic: A Case Report.

Malaria can present with clinical manifestations overlapping with thrombotic thrombocytopenic purpura (TTP). We present the case of a 55-year-old female who presented with abdominal pain, fever, confusion, dehydration, and recent travel to Nigeria. Laboratory investigations were remarkable for low hemoglobin, decreased platelets, and elevated lactate. Suspicion for TTP occurred when the patient's platelet count and hemoglobin progressively decreased along with acute kidney injury and confusion. There was an elevated ADAMTS13 antibody level and mildly reduced ADAMTS13 activity suggesting possible TTP. However, Plasmodium falciparum was seen on peripheral blood smears. Treatment with artemether-lumefantrine was initiated which led to improvement in parasitemia, platelet count, and anemia. The similarity between malaria and TTP is mostly explained by thrombotic microangiopathic anemia (TMA) present in both diseases. Awareness of the common pathogenesis of TMA in both diseases and clinical judgment are pivotal in determining the timely initiation of appropriate treatment.

In silico strategies for identifying therapeutic candidates against Acinetobacter baumannii: spotlight on the UDP-N-acetylmuramoyl-L-alanine-D-glutamate:meso-diaminopimelate ligase (MurE).

The opportunistic bacterium Acinetobacter baumannii, which belongs to ESKAPE group of pathogenic bacteria, is leading cause of infections associated with gram-negative bacteria. Acinetobacter baumannii causes severe diseases, such as VAP (ventilator-associated pneumonia), meningitis, and UTI (urinary tract infections) among the nosocomial infections contracted in hospitals. The high infection rate and growing resistance to the vast array of antibiotics makes it paramount to look for new therapeutic strategies against this pathogen. The most promising therapeutic targets are the proteins involved in the synthesis of peptidoglycan which is chief component of bacterial cell wall, MurE is one of those enzymes and is responsible for the addition of one unit of meso-diaminopimelic acid (meso-A2pm) to the nucleotide precursor, UDPMurNAc-L-Ala-D-Glu, and aids in the formation of crosslinker pentapeptide chain. The three-dimensional structure of MurE was modelled using homology modelling technique and then vHTS was performed using this model against Approved Drug Library on DrugRep server using AutoDock Vina. Out of 500 drug molecules, two were selected based on estimated binding affinity, interaction pattern, interacting residues, etc. The selected drug molecules are DB12887 (Tazemetostat) and DB13879 (Glecaprevir). Then, MD simulations were performed on native MurE and its complexes with ligands to examine their dynamical behaviour, stability, integrity, compactness, and folding properties. The protein-ligand complexes were then subjected to binding free energy calculations using the MM/PBSA-based binding free energy analysis and the values are -109.788 ± 8.03 and -152.753 ± 11.98 kcal for MurE-DB12887 and MurE-DB13879 complex, respectively. All the analysis performed on MD trajectories for the complexes of these ligands with protein provided plenty of dependable evidences to consider these molecules for inhibition of MurE enzyme from A. baumannii. Communicated by Ramaswamy H. Sarma.

Computational identification of candidate inhibitors for Dihydrofolate reductase in Acinetobacter baumannii.

Acinetobacter baumannii is one of the emerging causes of hospital acquired infections and this bacterium, due to multi-drug resistant and Extensive Drug resistant has been able to develop resistance against the antimicrobial agents that are being used to eliminate it. A.baumannii has been the cause of death in immune compromised patients in hospitals. Hence it is the urgent need of time to find potential inhibitors for this bacterium to cease its virulence and affect its survival inside host organisms. The Dihydrofolate reductase enzyme, which is an important biocatalyst in the conversion of Dihydrofolate to Tetrahydrofolate, is an important drug target protein. In the present study high throughput screening is used to identify the inhibitors of this enzyme. The prioritized ligand molecular candidates identified through virtual screening for the substrate binding site of the predicted model are Z1447621107, Z2604448220 and Z1830442365. The Molecular Dynamics Simulation study suggests that potential inhibitor of the Dihydrofolate reductase enzyme would prevent bacteria from completing its life cycle, affecting its survival. Finally the complexes were analysed for binding free energy of the Dihydrofolate reductase enzyme complexes with the ligands.

Exploration of potential hit compounds targeting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) from Acinetobacter baumannii: an in silico investigation.

The emergence of carbapenem-resistant Acinetobacter baumannii, a highly concerning bacterial species designated as a Priority 1: Critical pathogen by the WHO, has become a formidable global threat. In this study, we utilised computational methods to explore the potent molecules capable of inhibiting the IspC enzyme, which plays a crucial role in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. Employing high-throughput virtual screening of small molecules from the Enamine library, we focused on the highly conserved substrate binding site of the DXR target protein, resulting in the identification of 1000 potential compounds. Among these compounds, we selected the top two candidates (Z2615855584 and Z2206320703) based on Lipinski's rule of Five and ADMET filters, along with FR900098, a known IspC inhibitor, and DXP, the substrate of IspC, for molecular dynamics (MD) simulations. The MD simulation trajectories revealed remarkable structural and thermodynamic stability, as well as strong binding affinity, for all the IspC-ligand complexes. Furthermore, binding free energy calculations based on MM/PBSA (Molecular Mechanics/Poisson-Boltzmann Surface Area) methodology demonstrated significant interactions between the selected ligand molecules and IspC. Taking into consideration all the aforementioned criteria, we suggest Z2206320703 as the potent lead candidate against IspC. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03923-w.

SRF-deficient astrocytes provide neuroprotection in mouse models of excitotoxicity and neurodegeneration.

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These SrfGFAP-ERCKO astrocytes do not affect neuron survival, synapse numbers, synaptic plasticity or learning and memory. However, the brains of Srf knockout mice exhibited neuroprotection against kainic-acid induced excitotoxic cell death. Relevant to human neurodegenerative diseases, SrfGFAP-ERCKO astrocytes abrogate nigral dopaminergic neuron death and reduce ß-amyloid plaques in mouse models of Parkinson's and Alzheimer's disease, respectively. Taken together, these findings establish SRF as a key molecular switch for the generation of reactive astrocytes with neuroprotective functions that attenuate neuronal injury in the setting of neurodegenerative diseases.

A study on twitching motility dynamics in Ralstonia solanacearum microcolonies by live imaging.

Ralstonia solanacearum is a rod-shaped phytopathogenic bacterium that causes lethal wilt disease in many plants. On solid agar growth medium, in the early hour of the growth of the bacterial colony, the type IV pili-mediated twitching motility, which is important for its virulence and biofilm formation, is prominently observed under the microscope. In this study, we have done a detailed observation of twitching motility in R. solanacearum colony. In the beginning, twitching motility in the microcolonies was observed as a density-dependent phenomenon that influences the shape of the microcolonies. No such phenomenon was observed in Escherichia coli, where twitching motility is absent. In the early phase of colony growth, twitching motility exhibited by the cells at the peripheral region of the colony was more prominent than the cells toward the center of the colony. Using time-lapse photography and merging the obtained photomicrographs into a video, twitching motility was observed as an intermittent phenomenon that progresses in layers in all directions as finger-like projections at the peripheral region of a bacterial colony. Each layer of bacteria twitches on top of the other and produces a multilayered film-like appearance. We found that the duration between the emergence of each layer diminishes progressively as the colony becomes older. This study on twitching motility demonstrates distinctly heterogeneity among the cells within a colony regarding their dynamics and the influence of microcolonies on each other regarding their morphology.

Molecular dynamics simulations assisted investigation of phytochemicals as potential lead candidates against anti-apoptotic Bcl-B protein.

Due to the multifarious nature of cancer, finding a single definitive cure for this dreadful disease remains an elusive challenge. The dysregulation of the apoptotic pathway or programmed cell death, governed by the Bcl-2 family of proteins plays a crucial role in cancer development and progression. Bcl-B stands out as a unique anti-apoptotic protein from the Bcl-2 family that selectively binds to Bax which inhibits its pro-apoptotic function. Although several inhibitors are reported for Bcl-2 family proteins, no specific inhibitors are available against the anti-apoptotic Bcl-B protein. This study aims to address this research gap by using virtual screening of an in-house library of phytochemicals from seven anti-cancer medicinal plants to identify lead molecules against Bcl-B protein. Through pharmacokinetic analysis and molecular docking studies, we identified three lead candidates (Enterolactone, Piperine, and Protopine) based on appreciable drug-likeliness, ADME properties, and binding affinity values. The identified molecules also exhibited specific interactions with critical amino acid residues of the binding cleft, highlighting their potential as lead candidates. Finally, molecular dynamics simulations and MM/PBSA based binding free energy analysis revealed that Enterolactone (CID_114739) and Piperine (CID_638024) molecules were on par with Obatoclax (CID_11404337), which is a known inhibitor of the Bcl-2 family proteins.Communicated by Ramaswamy H. Sarma.

Identification of novel inhibitors against Med15a KIX domain of Candida glabrata.

Candida glabrata, the second most common cause of invasive fungal infections, exhibits multi-drug resistance to commonly used antifungal drugs. To counter this resistance, there is a critical need for novel antifungals. This study identifies small molecule inhibitors that target a three-helix bundle KIX domain in the Med15a Mediator subunit of Candida glabrata (CgMed15a KIX). This domain plays a crucial role by interacting with the Pleiotropic Drug Resistance transcription factor Pdr1, a key regulator of the multidrug resistance pathway in Candida glabrata. We performed high throughput computational screening of large chemical datasets against the binding sites of the CgMed15a KIX domain to identify novel inhibitors. We selected six potential candidates with high affinity and confirmed their binding with the CgMed15a KIX domain. A phytochemical compound, Chebulinic acid binds to the CgMed15a KIX domain with a KD value of 0.339 µM and shows significant inhibitory effects on the growth of Candida glabrata. Molecular dynamics simulation studies further revealed the structural stability of the CgMed15a KIX-Chebulinic acid complex. Thus, in conclusion, this study highlights Chebulinic acid as a novel potential antifungal compound against Candida glabrata.

A computational perspective towards the identification of promising lead molecules against 6-hydroxy-methyl dihydropterin pyrophosphokinase (HPPK) from Acinetobacter baumannii.

Acinetobacter baumannii is an ESKAPE pathogen that causes endocarditis, pneumonia, blood infections, urinary tract infections, and several other illnesses. In addition, it is mainly responsible for nosocomial infection-related mortality. Gram-negative A. baumannii bacterium (AYE Strain) has high MDR and XDR levels. Due to its function in synthesizing purines and amino acids, folic acid is a significant molecule necessary for the growth of bacteria. The metabolic pathway of folate production is therefore a potential therapeutic target to inhibit bacterial growth. In the current study, the three-dimensional model of 6-Hydroxy-methyl dihydropterinpyrophosphokinase (HPPK) was predicted and subsequently processed through a virtual high throughput screening (vHTS) against compounds from Enamine HTSC library, that could bind to its active site. Three lead candidates (Z73322064, Z354558542, and Z906123504) and a control molecule (7,8 dihydro-7,7-dimethyl-6-hydroxymethlypterin; Accession Number: DB02278) were identified using several screening criteria namely estimated binding affinity, estimated inhibition constant, drug-like properties, ADME properties, mode of binding, and interaction patterns of the screened compounds. The physiological behavior of ligand binding on the HPPK enzyme was then studied using molecular dynamics simulations of apo and ligand bound complexes. This study proposed the following three molecules: Z73322064, Z354338542, and Z906123504 as promising lead candidates against the substrate-binding site of the HPPK enzyme from A. baumannii using global, essential dynamics studies along with MM/PBSA based binding free energy analysis.Communicated by Ramaswamy H. Sarma.

Targeting multi-drug-resistant Acinetobacter baumannii: a structure-based approach to identify the promising lead candidates against glutamate racemase.

CONTEXT: Acinetobacter baumannii, one of the critical ESKAPE pathogens, is a highly resilient, multi-drug-resistant, Gramnegative, rod-shaped, highly pathogenic bacteria. It is responsible for almost 1-2% of all hospital-borne infections in immunocompromised patients and causes community outbreaks. Because of its resilience and MDR characteristics, looking for new strategies to check the infections related to this pathogen becomes paramount. The enzymes involved in the peptidoglycan biosynthetic pathway are attractive and the most promising drug targets. They contribute to the formation of the bacterial envelope and help to maintain the rigidity and integrity of the cell. The MurI (glutamate racemase) is one of the crucial enzymes that aid in the formation of the pentapeptide responsible for the interlinkage of peptidoglycan chains. It converts L-glutamate to D-glutamate, which is required to synthesise the pentapeptide chain. METHODS: In this study, the MurI protein of A. baumannii (strain AYE) was modelled and subjected to high-throughput virtual screening against the enamine-HTSC library, taking UDP-MurNAc-Ala binding site as the targeted site. Four ligand molecules, Z1156941329 (N-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxamide), Z1726360919 (1-[2-[3-(benzimidazol-1-ylmethyl)piperidin-1-yl]-2-oxo-1-phenylethyl]piperidin-2-one), Z1920314754 (N-[[3-(3-methylphenyl)phenyl]methyl]-8-oxo-2,7-diazaspiro[4.4]nonane-2-carboxamide) and Z3240755352 (4R)-4-(2,5-difluorophenyl)-1-(4-fluorophenyl)-1,3a,4,5,7,7a-hexahydro-6H-pyrazolo[3,4-b]pyridin-6-one), were identified to be the lead candidates based on Lipinski's rule of five, toxicity, ADME properties, estimated binding affinity and intermolecular interactions. The complexes of these ligands with the protein molecule were then subjected to MD simulations to scrutinise their dynamic behaviour, structural stability and effects on protein dynamics. The molecular mechanics/Poisson-Boltzmann surface area-based binding free energy analysis was also performed to compute the binding free energy of protein-ligand complexes, which offered the following values -23.32 ± 3.04 kcal/mol, -20.67 ± 2.91kcal/mol, -8.93 ± 2.90 kcal/mol and -26.73 ± 2.95 kcal/mol for MurI-Z1726360919, MurI-Z1156941329, MurI-Z3240755352 and MurI-Z3240755354 complexes respectively. Together, the results from various computational analyses utilised in this study proposed that Z1726360919, Z1920314754 and Z3240755352 could act as potential lead molecules to suppress the function of MurI protein from Acinetobacter baumannii.

Detailed Experimental and In Silico Investigation of Indomethacin Binding with Human Serum Albumin Considering Primary and Secondary Binding Sites.

The interaction of indomethacin with human serum albumin (HSA) has been studied here considering the primary and secondary binding sites. The Stern-Volmer plots were linear in the lower concentration range of indomethacin while a downward curvature was observed in the higher concentration range, suggesting the presence of more than one binding site for indomethacin inside HSA due to which the microenvironment of the fluorophore changed slightly and some of its fraction was not accessible to the quencher. The Stern-Volmer quenching constants (KSV) for the primary and secondary sites were calculated from the two linear portions of the Stern-Volmer plots. There was around a two-fold decrease in the quenching constants for the low-affinity site as compared to the primary binding site. The interaction takes place via a static quenching mechanism and the KSV decreases at both primary and secondary sites upon increasing the temperature. The binding constants were also evaluated, which show strong binding at the primary site and fair binding at the secondary site. The binding was thermodynamically favorable with the liberation of heat and the ordering of the system. In principle, hydrogen bonding and Van der Waals forces were involved in the binding at the primary site while the low-affinity site interacted through hydrophobic forces only. The competitive binding was also evaluated using warfarin, ibuprofen, hemin, and a warfarin + hemin combination as site markers. The binding profile remained unchanged in the presence of ibuprofen, whereas it decreased in the presence of both warfarin and hemin with a straight line in the Stern-Volmer plots. The reduction in the binding was at a maximum when both warfarin and hemin were present simultaneously with the downward curvature in the Stern-Volmer plots at higher concentrations of indomethacin. The secondary structure of HSA also changes slightly in the presence of higher concentrations of indomethacin. Molecular dynamics simulations were performed at the primary and secondary binding sites of HSA which are drug site 1 (located in the subdomain IIA of the protein) and the hemin binding site (located in subdomain IB), respectively. From the results obtained from molecular docking and MD simulation, the indomethacin molecule showed more binding affinity towards drug site 1 followed by the other two sites.

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study.

A. baumannii is a ubiquitously found gram-negative, multi-drug resistant bacterial species from the ESKAPE family of pathogens known to be the causative agent for hospital-acquired infections such as pneumonia, meningitis, endocarditis, septicaemia and urinary tract infections. A. baumannii is implicated as a contributor to bloodstream infections in approximately 2% of all worldwide infections. Hence, exploring novel therapeutic agents against the bacterium is essential. LpxA or UDP-N-acetylglucosamine acetyltransferase is an essential enzyme important in Lipid A biosynthesis which catalyses the reversible transfer of an acetyl group on the glucosamine 3-OH of the UDP-GlcNAc which is a crucial step in the biosynthesis of the protective Lipopolysaccharides (LPS) layer of the bacteria which upon disruption can lead to the elimination of the bacterium which delineates LpxA as an appreciable drug target from A. baumannii. The present study performs high throughput virtual screening of LpxA against the enamine-HTSC-large-molecule library and performs toxicity and ADME screening to identify the three promising lead molecules subjected to molecular dynamics simulations. Global and essential dynamics analysis of LpxA and its complexes along with FEL and MM/PBSA based binding free energy delineate Z367461724 and Z219244584 as potential inhibitors against LpxA from A. baumannii.

Structural and functional characterization of 1-deoxy-D-xylulose-5-phosphate synthase (DXS) from Acinetobacter baumannii: identification of promising lead molecules from virtual screening, molecular docking and molecular dynamics simulations.

The advent of multi drug resistance and extensive-drug resistance among various pathogens has caused a rise in nosocomial infections, which in turn has led to rising hospital-acquired infection-related mortality rates. Amongst them, carbapenem-resistant Acinetobacter baumannii is one of the most notorious bacterial species, categorized as a Priority 1: Critical pathogen by the WHO. Therefore, the discovery and development of novel antibiotics, as well as the identification of potential inhibitors, have become the need of the hour. In this study, we have employed computational methods to explore and identify molecules capable of inhibiting enzymes essential in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. The high throughput virtual screening of small molecules (Enamine Advanced Collection (AC) library) against the highly conserved substrate-binding site of the DXS target protein provided us with a total of 1000 molecules. The top four potential candidate molecules, namely-Z3353989070, Z3353989049, Z2295848528, and Z1685501455, alongside fluoropyruvate (control), a known inhibitor of DXS, was chosen for a molecular dynamic simulation study. The molecular dynamic simulation trajectories suggested high structural and thermodynamical stability and strong binding affinity of all the DXS-ligand complexes. Moreover, the MM/PBSA-based binding free energy calculations also exhibited strong interactions of the selected ligand molecules with DXS. In conclusion, we have found that all four molecules displayed better results and stronger binding affinity than the control. In the end, based on all the above-mentioned criteria, we have proposed Z3353989049 to be the promising lead candidate against DXS from A. baumannii.Communicated by Ramaswamy H. Sarma.

Shedding light on structure, function and regulation of human sirtuins: a comprehensive review.

Sirtuins play an important role in signalling pathways associated with various metabolic regulations. They possess mono-ADP-ribosyltransferase or deacylase activity like demalonylase, deacetylase, depalmitoylase, demyristoylase and desuccinylase activity. Sirtuins are histone deacetylases which depends upon nicotinamide adenine dinucleotide (NAD) that deacetylate lysine residues. There are a total of seven human sirtuins that have been identified namely, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7. The subcellular location of mammalian sirtuins, SIRT1, SIRT6, and SIRT7 are in the nucleus; SIRT3, SIRT4, and SIRT5 are in mitochondria, and SIRT2 is in cytoplasm. Structurally sirtuins contains a N-terminal, a C-terminal and a Zn+ binding domain. The sirtuin family has been found to be crucial for maintaining lipid and glucose homeostasis, and also for regulating insulin secretion and sensitivity, DNA repair pathways, neurogenesis, inflammation, and ageing. Based on the literature, sirtuins are overexpressed and play an important role in tumorigenicity in various types of cancer such as non-small cell lung cancer, colorectal cancer, etc. In this review, we have discussed about the different types of human sirtuins along with their structural and functional features. We have also discussed about the various natural and synthetic regulators of sirtuin activities like resveratrol. Our overall study shows that the correct regulation of sirtuins can be a good target for preventing and treating various diseases for improving the human lifespan. To investigate the true therapeutic potential of sirtuin proteins and their efficacy in a variety of pathological diseases, a better knowledge of the link between the structure and function of sirtuin proteins would be necessary.

Mask Adherence to Mask Mandate: College Campus Versus the Surrounding Community.

Adherence to masking recommendations and requirements continues to have a wide variety of impacts in terms of viral spread during the ongoing pandemic. As governments, schools, and private sector businesses formulate decisions around mask requirements, it is important to observe real-life adherence to policies and discern subsequent implications. The CDC MASCUP! observational study tracked mask-wearing habits of students on higher-education campuses across the country to collect stratified data about mask typologies, correct mask usage, and differences in behaviors at locations on a college campus and in the surrounding community. Our findings from a single institution include a significant adherence difference between on-campus (86%) and off-campus sites (72%) across the course of this study as well as a notable change in adherence at the on-campus sites with the expiration of a county-wide governmental mandate, despite continuance of a university-wide mandate. This study, completed on and around the campus of East Tennessee State University in Washington County TN, was able to pivotally extract information regarding increased adherence on campus versus the surrounding community. Changes were also seen when mask mandates were implemented and when they expired.

Isolation, characterisation, anticancer and anti-oxidant activities of 2-methoxy mucic acid from Rhizophora apiculata: an in vitro and in silico studies.

The main objective of the present study is to isolate and characterise the novel bioactive molecule, 2-methoxy mucic acid (4) from Rhizophora apiculate Blume under the Rhizophoraceae family. In this study, the 2-methoxy mucic acid (4) was isolated for the first time from the methanolic extract of the leaves of R. apiculata. Anticancer activity of 2-methoxy mucic acid (4) was evaluated against HeLa and MDA-MB-231 cancer cell lines and they displayed promising activity with IC50 values of 22.88283 ± 0.72 µg/ml in HeLa and 2.91925 ± 0.52 µg/ml in the case of MDA-MB-231, respectively. Furthermore, the antioxidant property of 2-methoxy mucic acid (4) was found to be (IC50) 21.361 ± 0.41 µg/ml. Apart from in vitro studies, we also performed extensive in silico studies (molecular docking and molecular dynamics simulation) on four critical antiapoptotic Bcl-2 family members (Bcl-2, Bcl-w, Bcl-xL and Bcl-B) towards 2-methoxy mucic acid (4). The results revealed that this molecule showed higher binding affinity towards Bcl-B protein (ΔG = -5.8 kcal/mol) and the structural stability of this protein was significantly improved upon binding of this molecule. The present study affords vital insights into the importance of 2-methoxy mucic acid (4) from R. apiculata. Furthermore, it opens the therapeutic route for the discovery of anticancer drugs. Research HighlightsThis is a first report on a bioactive compound identified and characterised; a novel 2-methoxy mucic acid derived from methanolic crude extract from the leaves of R. apiculata from ANI.Estimated binding free energy of 2-methoxy mucic acid is found to be -5.8 kcal/mol to the anti-apoptotic Bcl-B protein.2-methoxy mucic acid showed both significant anti-cancer and anti-oxidant activity.Communicated by Ramaswamy H. Sarma.

Isolation and biological evaluation 7-hydroxy flavone from Avicennia officinalis L: insights from extensive in vitro, DFT, molecular docking and molecular dynamics simulation studies.

The flavonoid based 7-hydroxy flavone (PubChem CID: 5281894; molecular formula: C15H10O3) molecule has been isolated for the first time from the methanolic extract from the leaves of Avicennia officinalis L. in the tropical mangrove ecosystem of Andaman and Nicobar Islands (ANI), India. The molecular structure of bioactive compound was characterized by spectroscopic analysis, including FT-IR, 1H, 13C NMR spectroscopy and ESI-HRMS and elucidated as 7-hydroxy flavone. An anticancer activity of isolated 7-hydroxy flavone was evaluated by in vitro study against two different human cancer cell lines namely, HeLa (cervical cells) and MDA-MB231 (breast cells) and they exhibited promising anticancer activity with IC50 values are 22.5602 ± 0.21 µg/mL and 3.86474 ± 0.35 µg/mL, respectively. The antioxidant property of 7-hydroxy flavone at a standard concentration of 50 µg, was found to be (IC50) 5.5486 ± 0.81 µg/mL. In summary, this investigation provides evidence that 7-hydroxy flavone exhibits both anticancer and antioxidant properties. Meanwhile, the antimicrobial activity ability of 7-hydroxy flavone were also evaluated using three Gram positive and two Gram negative strain exhibited no antimicrobial activities. Density-functional theory (DFT) studies confirm the structure is global minima in the PES, from the optimized geometry FMO and MESP map analyzed. Further, the molecular docking and molecular dynamics simulation studies result shows that 7-hydroxy flavone has the better binding ability with anti-apoptotic Bcl-2 protein with the estimated free energy of binding of -6.3 kcal/mol. This bioactive compound may be act as drug candidate for treating various kinds of cancers. HighlightsA 7-hydroxy flavone molecule has been isolated from Avicennia officinalis.The isolated pure compound was subjected to spectral analysis such as FT-IR, 1H NMR, 13C NMR spectral data and HRMS analysis for skeleton of the molecule.The anticancer activity of 7-hydroxy flavone studied against Cervical (HeLa) cancer cell lines and breast (MDA-MB231) cancer cell lines with the IC50 values of 22.5602 ± 0.21 µg/mL and 3.86474 ± 0.35 µg/mL), respectively.The antioxidant properties of 7-hydroxy flavone were found to be (IC50) 5.5486 ± 0.81 µg/mL at a standard concentration of 50 µg.DFT, molecular docking and MD simulation results explained that 7-hydroxy flavone could be the most promising candidate to inhibit the function of anti-apoptotic Bcl-2 protein in cancerous cell.Communicated by Ramaswamy H. Sarma.

Identification and prioritization of promising lead molecules from Syzygium aromaticum against Sortase C from Streptococcus pyogenes: an in silico investigation.

Sortases are extracellular transpeptidases that play an essential role in the adhesion of secreted proteins to the peptidoglycan layer of the cell wall of Gram-negative bacteria. Sortases are an important drug target protein due to their involvement in synthesizing the peptidoglycan cell wall of Streptococcus pyogenes, and these are not found in Homo sapiens. In this study, initially, we have performed protein sequence analysis to understand the sequential properties of Sortase C. Next, a comparative protein modeling approach was used to predict the three-dimensional model of Sortase C based on the crystal structure of Sortase C from Streptococcus pneumoniae. Virtual screening with an in-house library of phytochemicals from Syzygium aromaticum and molecular docking studies were performed to identify the promising lead molecules. These compounds were also analyzed for their drug-like and pharmacokinetic properties. Subsequently, the protein-ligand complexes of the selected ligands were subjected to molecular dynamics (MD) simulations to investigate their dynamic behavior in physiological conditions. The global and essential dynamics analyses result implied that the Sortase C complexes of the proposed three lead candidates exhibited adequate stability during the MD simulations. Additionally, the three proposed molecules showed favorable MM/PBSA binding free energy values ranging from -13.8 +/- 9.41 to -56.6 +/- 8.82 kcal/mol. After an extensive computational investigation, we have identified three promising lead candidates (CID:13888122, CID:3694932 and CID:102445430) against Sortase C from S. pyogenes. The result obtained from these computational studies can be used to screen and develop the inhibitors against Sortase C from S. pyogenes.Communicated by Ramaswamy H. Sarma.