Computational prediction of crucial genes involved in gonorrhea infection and neoplastic cell transformation: A multiomics approach.

Neisseria gonorrheae, the causative agent of genitourinary infections, has been associated with asymptomatic or recurrent infections and has the potential to form biofilms and induce inflammation and cell transformation. Herein, we aimed to use computational analysis to predict novel associations between chronic inflammation caused by gonorrhea infection and neoplastic transformation. Prioritization and gene enrichment strategies based on virulence and resistance genes utilizing essential genes from the DEG and PANTHER databases, respectively, were performed. Using the STRING database, protein‒protein interaction networks were constructed with 55 nodes of bacterial proteins and 72 nodes of proteins involved in the host immune response. MCODE and cytoHubba were used to identify 12 bacterial hub proteins (murA, murB, murC, murD, murE, purN, purL, thyA, uvrB, kdsB, lpxC, and ftsH) and 19 human hub proteins, of which TNF, STAT3 and AKT1 had high significance. The PPI networks are based on the connectivity degree (K), betweenness centrality (BC), and closeness centrality (CC) values. Hub genes are vital for cell survival and growth, and their significance as potential drug targets is discussed. This computational study provides a comprehensive understanding of inflammation and carcinogenesis pathways that are activated during gonorrhea infection.

ß-keto amyrin isolated from Cryptostegia grandiflora R. br. inhibits inflammation caused by Daboia russellii viper venom: Direct binding of ß-keto amyrin to phospholipase A2.

The search for mechanism-based anti-inflammatory therapies is of fundamental importance to avoid undesired off-target effects. Phospholipase A2 (PLA2) activity is a potential molecular target for anti-inflammatory drugs because it fuels arachidonic acid needed to synthesize inflammation mediators, such as prostaglandins. Herein, we aim to investigate the molecular mechanism by which ß-keto amyrin isolated from a methanolic extract of Cryptostegia grandiflora R. Br. Leaves can inhibit inflammation caused by Daboia russellii viper (DR) venom that mainly contains PLA2. We found that ß-keto amyrin neutralizes DR venom-induced paw-edema in a mouse model. Molecular docking of PLA2 with ß-keto amyrin complex resulted in a higher binding energy score of -8.86 kcal/mol and an inhibition constant of 611.7 nM. Diclofenac had a binding energy of -7.04 kcal/mol and an IC50 value of 620 nM, which predicts a poorer binding interaction than ß-keto amyrin. The higher conformational stability of ß-keto amyrin interaction compared to diclofenac is confirmed by molecular dynamics simulation. ß-keto amyrin isolated from C. grandiflora inhibits the PLA2 activity contained in Daboia russellii viper venom. The anti-inflammatory property of ß-keto amyrin is due to its direct binding into the active site of PLA2, thus inhibiting its enzyme activity.

Marmesin and Marmelosin Interact with the Heparan Sulfatase-2 Active Site: Potential Mechanism for Phytochemicals from Bael Fruit Extract as Antitumor Therapeutics.

Human heparan sulfatase-2 (HSULF-2) is an oncoprotein overexpressed in the surface of all types of tumor cells and its activity plays a critical role in cancer survival and progression. Our previous studies have shown that bael fruit extract, containing marmesin and marmelosin, inhibits the HSULF-2 activity and kills breast tumor cells, but the mechanism of these processes remains fairly known mainly because the HSULF-2's 3D structure is partially known. Herein, we aimed at providing an in silico molecular mechanism of the inhibition of human HSULF-2 by phytochemicals from bael fruit extract. Pharmacokinetic parameters of the main phytochemicals contained in the bael fruit extract, sequence-based 3D structure of human HSULF-2, and the interaction of bael fruit's phytochemicals with the enzyme active site was modeled, evaluated, and verified. Docking studies revealed marmesin and marmelosin as potential inhibitors with binding score -8.5 and -7.7 Kcal/mol; these results were validated using molecular dynamics simulations, which exhibited higher stability of the protein-ligand complexes. Taking together, with our earlier in vitro data, our computational analyses suggest that marmesin and marmelosin interact at the active site of HSULF-2 providing a potential mechanism for its inhibition and consequent antitumor activity by phytochemicals contained in the bael fruit extract.

RNR inhibitor binding studies of Chlamydia felis: insights from in silico molecular modeling, docking, and simulation studies.

Chlamydia felis is the primary cause of chronic conjunctivitis without respiratory infections in cats, making conjunctiva as its primary target. It is a Gram-negative obligate intracellular bacterium that cannot survive outside the host cell. C. felis can be found worldwide and its zoonotic potential is a known phenomenon. The scope of zoonoses, its scale, and their impact experiencing today has no historical precedence. Among the identified 1415 human pathogens 868 have a zoonotic origin making it to 61%. Although with appropriate drug administration there are instances of re-occurrence of chlamydial infections, the emergence of heterotypic antimicrobial resistance to antibiotics targeting rRNA due to mutations has further complicated the diagnosis and treatment of chlamydial infections. Ribonucleotide-diphosphate reductase subunit beta (RNR) is one of the crucial target proteins of the bacterial pathogens essential in the synthesis of deoxyribonucleotides. Our current study primarily focuses on modeling the target structure through homology modeling. Further, the validated model is complexed with the specific inhibitor Cladribine through sequence-based ligand search. Docking of the identified ligand was performed to identify the different modes of interactions with amino acids present in the prioritized binding pockets. Validation of the binding modes is carried out through molecular dynamics (MD) simulations for the best binding pose with a high binding score. MD simulation study demonstrated the stability of the docked complex considered in this study. The findings from this study may be helpful in drug repurposing and novel drug research in the scenario of resistance to currently practiced antibiotics.Communicated by Ramaswamy H. Sarma.

Fabricate, advancement, molecular docking and DNA reactivity of preferred divalent metal(II) complexes attributing (E)-N'-((6-hydroxybenzo[d]oxazol-5-yl) methylene)isonicotinohydrazide.

A series of metal(II) complexes (M=Co (II), Ni(II) and Cu(II)) supported by Schiff base ligand (L=(E)-N'-((6-hydroxybenzo[d]oxazol-5-yl)methylene)isonicotinohydrazide) has been designed and developed from condensation of 6-hydroxybenzo[d]oxazole-5-carbaldehyde and isoniazid. The ligand (H2L) and its metal(II) complexes were structurally characterized utilizing a variety of physicochemical and spectroscopic approaches. The study shows that Schiff bases (H2L) act as monobasic tridentate ONO ligand and conform to octahedral geometry according to the general formula [M(HL)2]. Furthermore, the interaction of these complexes with CT-DNA was investigated at pH = 7.2, utilizing UV-visible absorption, and viscosity measurement. In order to determine the mechanism of binding of the metal(II) complexes to the B-DNA dodecamer, docking studies were conducted using an AutoDock Vina 1.2.0 tool. The photo induced cleavage reveals that the ligand (H2L) and its complexes have UV-visible photo nuclease properties against pUC19 DNA by agarose gel electrophoresis technique. Studies showed that the complexes evaluated firmly bind to CT-DNA via intercalative mode and provides a distinctive pattern of DNA binding.