The outbreak of novel SARS-CoV-2 virion has wreaked havoc with a high prevalence of respiratory illness and high transmission due to a vague understanding of the viral antigenicity augmenting dire challenge to public health globally. This viral member requisite the expansion of diagnostic and therapeutic tools to track its transmission and confront through vaccine development. Therefore, prophylactic strategies are mandatory. Virulence-related spike proteins can be the desirable candidate befitting computational design of vaccines targeting SARS-CoV-2 followed by meteoric development of immune epitopes. This study aims to characterize Spike protein using the existing knowledge related to the immunological profile of SARS-CoV-2 to predict immunogenic epitopes based on antigenicity, allergenicity, toxicity, immunogenicity, and population coverage. Applying in-silico approaches, a set of twenty-four B lymphocyte-based epitopes and forty-six T lymphocyte-based epitopes (MHC-I and MHC-II) were selected. The predicted epitopes were evaluated for their intrinsic properties. Physico-chemical characterization of epitopes qualify them for further in vitro and in vivo analysis pre-requisite vaccine development. This study presents a set of screened epitopes that binds to the HLA- specific allelic proteins that can be employed for designing a multi-epitopic peptide vaccine construct (MEPVC) against SARS-CoV-2 that will confer vaccine-induced protective immunity due to its structural stability.

Gamma secretase (GS) is an important therapeutic target in anticancer drug discovery. Increased GS activity activates notch signaling pathway which is associated with cancer stemness and drug resistance in cancer cells. A total of 69,075 natural and their derivative compounds were screened to identify the lead compound on the basis of in silico GS catalytic domain binding potential and in vitro selective anticancer efficacy. STOCK1N-23234 showed higher dock score (-11.82) compared to DAPT (-9.2) in molecular docking experiment and formed hydrogen bond with the key amino acid (Asp385) involve in catalysis process. Molecular dynamics (MD) simulation parameters (RMSD, RMSF, Rg, SASA and hydrogen bond formation) revealed that the STOTCK1N-23234 formed structurally and energetically stable complex with the GS catalytic domain with lower binding energy (-22.79 kcal/mol) compared to DAPT (-16.22 kcal/mol). STOCK1N-23234 showed better toxicity (up to 60%) against colon and breast cancer cells (HCT-116 and MDA-MB-453) at 1-70 µM concentration. Interestingly, STOCK1N-23234 did not showed cytotoxicity against human normal breast cells (MCF-10A). STOCK1N-23234 treatment significantly decreased sphere formation, notch promoter activity, and transcription of notch target genes (Hes-1 and Hey-1) in HCT-116 cells derived colonosphere. Confocal microscopy revealed that STOTCK1N-23234 treatment at test concentration induced apoptosis related morphological changes, reduced mitochondria membrane potential and increased reactive oxygen species production in HCT-116 cells compared to non-treated cells. In conclusion, STOCK1N-23234 is a novel lead natural anticancer compound which requires in depth validation in cancer preclinical models.

Cancer is characterized by genetic instability due to accumulation of somatic mutations in the genes which generate neoepitopes (mutated epitopes) for targeting by Cytotoxic T lymphocytes (CTL). Breast cancer has a high transformation rate with unique composition of mutational burden and neoepitopes load that open a platform to designing a neoepitopes-based vaccine. Neoepitopes-based therapeutic cancer vaccines designed by neoantigens have shown to be feasible, nontoxic, and immunogenic in cancer patients. Stimulation of CTL by neoepitope-based vaccine of self-antigenic proteins plays a key role in distinguishing cancer cells from normal cells and selectively targets only malignant cells. A neoepitopes-based vaccine to combat breast cancer was designed by combining immunology and bioinformatics approaches. The vaccine construct was assembled by the fusion of CTL neoepitopes, helper sequences (used for better separation of the epitopes), and adjuvant together with linkers. The neoepitopes were identified from somatic mutations in the MUC16, TP53, RYR2, F5, DNAH17, ASPM, and ABCA13 self-antigenic proteins. The vaccine construct was undertaken to study the immune simulations (IS), physiochemical characteristics (PP), molecular docking (MD) and simulations, and cloning in appropriate vector. Together, these parameters establish safety, stability, and a strong binding affinity against class I MHC molecules capable of inducing a complete immune response against breast cancer cells.Communicated by Ramaswamy H. Sarma.

Immunogenicity of gliadin peptides in celiac disease (CD) is majorly determined by the pattern of molecular interactions with HLA-DQ and T-cell receptors (TCR). Investigation of the interactions between immune-dominant gliadin peptides, DQ protein, and TCR are warranted to unravel the basis of immunogenicity and variability contributed by the genetic polymorphisms. Homology modeling of HLA and TCR done using Swiss Model and iTASSER, respectively. Molecular interactions of eight common deamidated immune-dominant gliadin with HLA-DQ allotypes and specific TCR gene pairs were evaluated. Docking of the three structures was performed with ClusPro2.0 and ProDiGY was used to predict binding energies. Effects of known allelic polymorphisms and reported susceptibility SNPs were predicted on protein–protein interactions. CD susceptible allele, HLA-DQ2.5 was shown to have considerable binding affinity to 33-mer gliadin (Δ G = − 13.9; K d = 1.5E − 10) in the presence of TRAV26/TRBV7. Higher binding affinity was predicted (Δ G = − 14.3, K d = 8.9E − 11) when TRBV28 was replaced with TRBV20 paired with TRAV4 suggesting its role in CD predisposition. SNP rs12722069 at HLA-DQ8 that codes Arg76α forms three H-bonds with Glu12 and two H-bonds with Asn13 of DQ2 restricted gliadin in the presence of TRAV8-3/TRBV6 . None of the HLA-DQ polymorphisms was found to be in linkage disequilibrium with reported CD susceptibility markers. Haplotypic presentations of rs12722069-G, rs1130392-C, rs3188043-C and rs4193-A with CD reported SNPs were observed in sub-ethnic groups. Highly polymorphic sites of HLA alleles and TCR variable regions could be utilized for better risk prediction models in CD. Therapeutic strategies by identifying inhibitors or blockers targeting specific gliadin:HLA-DQ:TCR binding sites could be investigated.

Cancer signaling networks are complex, involving gene regulation, signaling, and cell metabolism. Alterations in these networks caused by different mutations can lead to malignancy. We aim to evaluate these networks' computational models that allow us to understand their complex behavior better. This study aims to validate the correlation between cancer signaling pathways' complexity (clustering coefficient) and cancer epidemiological data sets, including cancer incidence, death rate, and lifetime risk. These results support the hypothesis that network complexity directly indicates cancer risk. Understanding the differential behavior of regulatory networks during health, disease, and in response to drugs is crucial for enhancing drug development efforts, identifying new targets, delineating off-target effects, predicting disease, developing combinatorial drug regimens, and developing personalized treatments targeted at the molecular level.

Peptide deformylase (PDF), a metalloenzyme is an important and attractive target in antibacterial drug discovery. It removes the N-formyl group from the nascent peptide and generates a mature N-terminal end of the protein molecule. Acarbose is an FDA-approved microbial origin anti-diabetic drug and is known to alter the gut microbiota in clinical studies. The present study first time identifies the binding efficacy of acarbose isolated from a natural source against PDF. We performed molecular docking and molecular dynamics (MD) simulation studies to check the binding efficacy of acarbose with the catalytic site of Helicobacter pylori PDF. Molecular docking results of acarbose complexed with PDF showed a good docking score (-12.55 kcal/mole) in comparison to standard drug bind with PDF (-8.99 kcal/mole). Interaction with the amino acids (Gly95, Glu139, His138, Gly46 and Glu940) and metal ion present at the catalytic site of the test protein was found to be common in PDF during interaction with the acarbose and actinonin. Various parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape and principal component analysis showed that the acarbose form stable and energetically stable complex with PDF in comparison to actinonin. Taken together, our study concludes that the acarbose possesses significant efficacy in binding at the catalytic site of H. pylori PDF. Acarbose is a FDA-approved anti-diabetic drug thus its antibacterial efficacy may be directly studied in clinical trials. Further, the in vitro and in vivo studies are needed to study the antibacterial mode of action of acarbose in physiological conditions.

Notch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment.

Gamma secretase (GS) produces Notch Intracellular Domain (NICD) by trans-membrane cleavage of notch receptor. The NICD enters the nucleus and activates the notch signaling pathway (NSP) by activating notch-responsive gene transcription. Hyperactivation of NSP is related to cancer aggressiveness, therapy resistance, and poor therapy outcome, and decreased overall disease-free survival in patients. Till date, none of the GS inhibitors (GSI) has been clinically approved due to their toxicity in patients. Thus in the present study, we explored the GS catalytic site binding potential of hesperidin (natural flavone glycoside) and its effect on notch responsive gene expression in HCT-116 cells. Molecular docking, MM-GBSA binding energy calculations, and molecular dynamics (MD) simulation experiments were performed to study the GS catalytic site binding potential of hesperidin. The compound showed better GS catalytic site binding potential at the active site compared to experimentally validated GSI, N-N-(3, 5-Difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT) in molecular docking and MM-GBSA experiments. MD simulation results showed that hesperidin forms stable and energetically favorable complex with gamma secretase in comparison to standard inhibitor (DAPT)-GS complex. Further, in vitro experiments showed that hesperidin inhibited cell growth and sphere formation potential in HCT-116 cells. Further, hesperidin treatment altered notch responsive genes (Hes1, Hey1, and E-cad) and cancer stemness/self-renewal markers expression at transcription levels. In conclusion, hesperidin produces toxicity in HCT-116 cells and decreases colonosphere formation by inhibiting transcription of notch signaling pathway target genes and stemness markers.

The outbreak of novel SARS-CoV-2 virion has wreaked havoc with a high prevalence of respiratory illness and high transmission due to a vague understanding of the viral antigenicity, augmenting the dire challenge to public health globally. This viral member necessitates the expansion of diagnostic and therapeutic tools to track its transmission and confront it through vaccine development. Therefore, prophylactic strategies are mandatory. Virulent spike proteins can be the most desirable candidate for the computational design of vaccines targeting SARS-CoV-2, followed by the meteoric development of immune epitopes. Spike protein was characterized using existing bioinformatics tools with a unique roadmap related to the immunological profile of SARS-CoV-2 to predict immunogenic virulence epitopes based on antigenicity, allergenicity, toxicity, immunogenicity, and population coverage. Applying in silico approaches, a set of twenty-four B lymphocyte-based epitopes and forty-six T lymphocyte-based epitopes were selected. The predicted epitopes were evaluated for their intrinsic properties. The physico-chemical characterization of epitopes qualifies them for further in vitro and in vivo analysis and pre-requisite vaccine development. This study presents a set of screened epitopes that bind to HLA-specific allelic proteins and can be employed for designing a peptide vaccine construct against SARS-CoV-2 that will confer vaccine-induced protective immunity due to its structural stability.

Gamma secretase (GS) activates notch signalling pathway (NSP) by liberating the truncated notch intracellular domain (NICD). The NSP is associated with the cancer development and progression, which makes GS a potential therapeutic target. Now day's marine compounds emerged as a major source of bioactive entity. The NSP inhibition potential of marine-algal compounds has not yet been studied. Thus, in the present study, we have used molecular docking, molecular dynamics (MD) simulations, principal component analysis (PCA) and free energy and binding energy calculations to identify the potential GS inhibitors of marine-algal origin. Laminarin showed better docking score (-12.72) compared to the known GS inhibitor DAPT (-9.2). Laminarin formed H-Bond interaction with the Asp257 and Asp385 required for the catalytic cleavage activity of gamma-secretase. It potentially stabilised the structural parameters (RMSD, RMSF, Rg and SASA) of GS catalytic subunit compared to DAPT during the MD simulation. The PCA and free energy calculation revealed conformationally and energetically stable Laminarin-GS complex formation. Laminarin showed lower binding energy (-44.75 kcal/mol) with GS catalytic subunit than DAPT (-20.92 kcal/mol). In conclusion, the present study provides a marine-algal compound as a novel potential GS inhibitor, which requires further validation in experimental model.

The α-amylase is regarded as a promising drug target for diabetes mellitus-type II. Hence, inhibiting α-amylase activity is a potential drug discovery approach for treating this chronic metabolic disorder. The present study explores the structural requirements and understands the inhibition mechanism of the novel developed indole-based derivatives as α-amylase inhibitors through 3D-QSAR, molecular docking, ADMET, and molecular dynamics (MD) simulation. The 3D-QSAR study showed good statistical reliability for two developed predictive models; CoMFA and CoMSIA. Through a deep investigation of docking analysis, detailed interactions with α-amylase of the most active compound 7 were explored. Four new indole derivatives were designed based on the contour maps and docking analysis, with significantly higher inhibitory activity than the molecules in the dataset. The selected molecules were evaluated for pharmacokinetic properties, showing a reasonably good ADMET profile. Furthermore, a 20-ns MD simulation of selected compounds bound to α-amylase was performed to ensure stability during simulation further. Greater stability of the designed molecule-protein complex A1 was found. The present findings shed light on the binding mode and the interactions between newly designed compounds, especially compound A1 and α-amylase and may be beneficial for drug development efforts targeting type-II diabetes.

The single crystalline diethyl 3,3[Formula: see text]-[(2,4-dichlorophenyl)methylidene]bis(1H-indole-2-carboxylate) (D32DMBC) samples are fully grown-up in a proper and in a successful manner by the prevailing slowly evaporating methodology. The lattice cell frameworks by XRD modus operandi also corroborated that the D32DMBC crystal system is monoclinic in nature. The structural properties by a conceptual way authenticate the elucidation and also the proper vindication for bond parameters. The nano influx is 3.2768 micron and the film-coated influx of 2.9977 microns as a mid-value between the macro as well as the nano assessment is suitable for electronic filters by D32DMBC crystals, and also used for tribological-coated utility as well as in frequency multipliers. Diabetes mellitus is the repetitive disease in the way of life and sustaining approach of D32DMBC — organic crystals are properly, accurately experimented by the use of the software pertaining to the D32DMBC by docking effect. The affinity inhibitory activity of A74DME and exploratory molecule of D32DMBC are −8.1[Formula: see text]kJ/mole and −8.4[Formula: see text]kJ/mole correspondingly. The computational effect of Hirshfeld portrays the internal/external fields as well as the electron higher/lower profile in the shape index proviso for optical utility identification and proper electronic utility.

The present study reports anticancer and antioxidant activities of Callistemon lanceolatus bark extracts. Anticancer activity was studied against MDA-MB-231 cells. Antioxidant assessment of the chloroform and methanol extracts showed considerable free radical scavenging, metal ion chelating, and reducing power potential. Chloroform extract exhibited potent inhibition of cancer cell proliferation in MTT assay (IC 50 9.6 μg/ml) and promoted programmed cell death. Reactive oxygen species (ROS) generation, mitochondria membrane potential (MMP) disruption ability, and nuclear morphology changes were studied using H 2 -DCFDA, JC-1, and Hoechst dyes, respectively, using confocal microscopy. Apoptotic cells exhibited fragmented nuclei, increased ROS generation, and altered MMP in dose- and time-dependent manner. Chloroform extract upregulated the BAX-1 and CASP3 mRNA expression coupled with downregulation of BCL-2 gene. Further, in silico docking of phytochemicals present in C. lanceolatus with anti-apoptotic Bcl-2 protein endorsed apoptosis by its inhibition and thus corroborated the experimental findings. Obatoclax, a known inhibitor of Bcl-2 was used as a reference compounds.

Abstract Aromatase, a cytochrome P450 enzyme, is responsible for the conversion of androgens to estrogens, which fuel the multiplication of cancerous cells. Inhibition of estrogen biosynthesis by aromatase inhibitors (AIs) is one of the highly advanced therapeutic approach available for the treatment of estrogen-positive breast cancer. Biphenyl moiety aids lipophilicity to the conjugated scaffold and enhances the accessibility of the ligand to the target. The present study is focused on the investigation of, the mode of binding of biphenyl with aromatase, prediction of ligand-target binding affinities, and pharmacophoric features essential for favorable for aromatase inhibition. A multifaceted 3D-QSAR (SOMFA, Field and Gaussian) along with molecular docking, molecular dynamic simulations and pharmacophore mapping were performed on a series of biphenyl bearing molecules (1–33) with a wide range of aromatase inhibitory activity (0.15–920 nM). Among the generated 3D-QSAR models, the Force field-based 3D-QSAR model (R 2 = 0.9151) was best as compared to SOMFA and Gaussian Field (R 2=0.7706, 0.9074, respectively). However, all the generated 3D-QSAR models were statistically fit, robust enough, and reliable to explain the variation in biological activity in relation to pharmacophoric features of dataset molecules. A four-point pharmacophoric features with three acceptor sites (A), one aromatic ring (R) features, AAAR_1, were obtained with the site and survival score values 0.890 and 4.613, respectively. The generated 3D-QSAR plots in the study insight into the structure–activity relationship of dataset molecules, which may help in the designing of potent biphenyl derivatives as newer inhibitors of aromatase. Communicated by Ramaswamy H. Sarma

Aberrant activation of Notch signaling pathway plays an important role in breast cancer development, progression, and stem cell renewal. Activation of Notch signaling is triggered by the interaction of Notch receptors with different ligands expressed on neighboring cells that bind and induce a second cleavage by a membrane-tethered metalloprotease. The remaining membrane-bound fragment is cleaved by γ-secretase (GS) releasing the Notch Intracellular Domain (NICD), which translocate to the nucleus to activate the expression of Notch target genes. Current indirect approaches to inhibit Notch signaling are based on agents that bind to GS substrates. In the search of novel Notch signaling inhibitor(s), we screened a number of plant flavonoids for their binding potential to GS substrate. Our in-silico study identified kurarinone (KU), a lavandulyl flavanone, having ability to bind to GS complex. The KU-GS complex was structurally and energetically stable during the molecular dynamics simulation period. Interestingly, dose and time dependent toxicity of KU was observed in T47D and MDA-MB-231 breast cancer cells at 1-25µM concentration. KU treatment of cells led to inhibition in cyclin D1 expression, arrest of cells in the G1 phase of the cell cycle and subsequently undergoes apoptosis. KU-mediated apoptosis was a result of altered mitochondria membrane potential and increased ROS production. In dual-luciferase Notch promoter assay, KU inhibited GS-mediated NICD production in transfected HEK293 cells. Furthermore, KU treatment decreased the mammosphere formation potential of MCF-7 cells through altered gene expression involved in self-renewal and stemness. KU treated MDA-MB-231 cells and MCF-7 derived mammosphere showed downregulation of Notch signaling through alteration in the expression of downstream genes such as Hey1, Hes1, and E-cadherin at both transcript and protein levels. Taken together, the present study identified KU as a novel natural Notch signaling inhibitor that could provide a novel and safer approach for the treatment of breast cancer through reduction in stemness and self-renewal properties. Citation Format: Prem Prakash Kushwaha, Mohd Shuaib, Kumari Sunita Prajapati, Atul Kumar Singh, Mahesh Kulharia, Shashank Kumar, Sanjay Gupta. Kurarinone, a natural notch signaling inhibitor and modulator of breast cancer stemness. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4955.

MicroRNAs (miRNAs) play critical role in normal breast development and their altered expression may lead to breast cancer. Identification of new miRNAs allows us to understand the normal physiological process and associated disease pathophysiology. In the present study we identify the novel miRNAs in withaferin A treated breast normal cells (MCF-10A) using small RNA sequencing. The pathophysiological potential of the identified miRNAs was checked by studying their expression pattern in MDA-MB-231 and MCF-7 breast cancer cells using qRT-PCR technique. The secondary/tertiary structure of the identified miRNAs, target gene enrichment in Gene Ontology terms and KEGG pathway, miRNA-mRNA interaction of the sorted target genes, miRNA-mRNA/miRNA-argonaute protein/miRNA-mRNA-argonaute protein interaction and stability, were studied using bioinformatics tools/software, and molecular dynamics simulations. Hsa-miR-N88585 and hsa-miR-N461089 were identified and validated as novel miRNAs in normal breast cells. Up-expression of identified miRNAs in MDA-MB-231 and MCF-7 cells indicates their oncogenic nature. Identified target genes were enriched in classical signaling pathways (AMPK and Ras) and important GO terms. PLXDC2, BHLHE40, ARMC8, and PECAM1, CDC27, KCNK3 genes were sorted as putative targets for hsa-miR-N88585 and hsa-miR-N461089, respectively. MD simulation revealed stable hsa-miR-N88585/hsa-miR-N461089-AGO protein complex formation which indicates their further processing. In conclusion, the study identifies hsa-miR-N88585 and hsa-miR-N461089 as novel miRNAs in breast normal cells which are significantly inversely expressed in breast cancer cells. Further experiments are required to study the role of identified novel miRNAs in normal breast development and pathophysiology of breast cancer.

This research aims to screen out the effective bioactive compounds from Coriander (Coriandrum sativum L.), which may be novel potential inhibitors of Eubacterium rectale for the prevention of colorectal cancer (CRC). A series of 8 coriander-derived chemical compounds previously assessed for their anti-inflammatory, antioxidant, and antidiabetic activities were tested against Carbohydrate ABC transporter substrate-binding protein and compared to the standard inhibitor Acarbose, to support their use as novel Eubacterium rectale inhibitors. Herein, these derivatives were submitted to a thorough analysis of docking studies, in which detailed interactions of the selected phytocompounds with carbohydrate ABC transporter substrate-binding protein were revealed. Molecular docking analysis recommends Rutin, Gallocatechin, and Epigallocatechin as the most potential Eubacterium rectale inhibitors among the eight selected phytochemical compounds. Subsequently, the stability of the three selected phytochemical complexes was checked using molecular dynamics (MD) simulation at 100 ns and Molecular Mechanics combined with Poisson-Boltzmann Surface Area (MM-PBSA). The results show quite good stability for Rutin and Gallocatechin. In silico ADMET prediction was performed on the selected compounds, and the findings revealed a reasonably good ADMET profile for both Rutin and Gallocatechin. The current findings predict that Gallocatechin could be a better CRC preventive natural compound, and, further in vitro, in vivo and clinical studies may confirm its therapeutic potential. Communicated by Ramaswamy H. Sarma

Rutin, a natural flavonol, can modulate molecular signaling pathways and has considerable potential in cancer treatment. However, little is known about the effect of rutin on the notch signaling pathway (NSP) in cancer and cancer stem-like cells. In this study, we explored the effect of rutin on gamma secretase (GS, a putative notch signaling target) inhibition mediated NICD (Notch Intracellular Domain) production in colon cancer cells. Molecular docking, MM-GBSA, and Molecular dynamics (MD) simulation experiments were performed to check rutin's GS catalytic site binding potential. The HCT-116 colon cancer and cancer stem-like cells (colonospheres) were utilized to validate the in silico findings. The NICD production, notch promoter assay, expression of notch target genes, and cancer stemness/self-renewal markers were studied at molecular levels. The results were compared with the Notch-1 siRNA transfected test cells. The in silico study revealed GS catalytic site binding potential in rutin. The in vitro results showed a decreased NICD formation, an altered notch target gene (E-cad, Hes-1, and Hey-1) expression, and a reduction in stemness/self-renewal markers (CD44, c-Myc, Nanog, and Sox2) in test cells in a time and dose-dependent manner. In conclusion, rutin inhibits the notch signaling pathway and reduces the stemness/self-renewal property in colon cancer cells and the colonospheres by targeting gamma secretase. The clinical efficacy of rutin in combination therapy in colon cancer may be studied in the future.

Background: In bacteria, peptide deformylase (PDF), a metalloenzyme, removes N-formyl methionine from a nascent protein, which is a critical step in the protein maturation process. The enzyme is ubiquitously present in bacteria and possesses therapeutic target potential. Acarbose, an FDA-approved antidiabetic drug, is an alpha-glucosidase inhibitor of microbial origin. Clinical studies indicate that acarbose administration in humans can alter gut microbiota. As per the best of our knowledge, the antibacterial potential of acarbose has not been reported. Objective: The present study aimed to check the binding ability of acarbose to the catalytic site of E. coli PDF and assess its in vitro antibacterial activity. Methods: Molecular docking, molecular dynamic (MD) simulation, and MM-PBSA experiments were performed to study the binding potential of the catalytic site, and a disc diffusion assay was also employed to assess the antibacterial potential of acarbose. Results: Acarbose was found to form a hydrogen bond and interact with the metal ion present at the catalytic site. The test compound showed a better docking score in comparison to the standard inhibitor of PDF. MD simulation results showed energetically stable acarbose-PDF complex formation in terms of RMSD, RMSF, Rg, SASA, and hydrogen bond formation throughout the simulation period compared to the actinonin-PDF complex. Furthermore, MM-PBSA calculations showed better binding free energy (∆G) of acarbose PDF than the actinonin-PDF complex. Moreover, acarbose showed in vitro antibacterial activity. Conclusion: Acarbose forms conformational and thermodynamically stable interaction with the E. coli peptide deformylase catalytic site. Results of the present work necessitate in-depth antimicrobial potential studies on the effect of acarbose on drug resistance and nonresistant bacteria.

Abstract Matrix metalloproteinase-2 (MMP2), an extracellular matrix remodulating protein’s increased activity causes cancer-metastasis. Potential MMP2 inhibitors showed sever side-effects in clinical trials. Present study is focused on identification natural MMP2 inhibitor by applying molecular docking, MM-GBSA binding energy estimation and molecular dynamics (MD) simulations. Commercially available flavonoid compound library was used to screen the molecules potentially binding with catalytic domain of MMP2 protein compared to standard MMP2 inhibitor ARP100. Naringin dihydrochalcone (NDC) showed interaction with the important residues (His120, Leu82 and Val117) present at the MMP2 catalytic domain in comparison to known inhibitor ARP100 (dock score ≈ −13 and −8 kcal/mole respectively). Lower ligand-protein binding energy (-67.31 kcal/mole) obtained in MM-GBSA and the MD simulation trajectory analysis showed significant stable and energetically favourable binding of NDC at the catalytic site of MMP2. In conclusion, anti-metastatic potential of NDC should be validated in in vitro and in vivo experiments. Graphical Abstract