As a growing number of clinical isolates Mycobacterium abscessus are resistant to most antibiotics, new treatment options that effective against these drug-resistant strains desperately needed. The majority the linkages in cell wall peptidoglycan M. synthesized by nonclassical transpeptidases, namely, l,d-transpeptidases. Emerging evidence suggests enzymes represent molecular vulnerability this pathogen. Recent studies have demonstrated inhibition carbapenem class β-lactams determines their...

Tyrosinase is a key enzyme in melanin synthesis and widely distributed plants animals tissues. In mammals, this related to pigment production, involved wound healing, primary immune response it can also contribute catecholamines the brain. Consequently, tyrosinase represents an attractive selective target field of medicine, cosmetics bio-insecticides. paper, experimental kinetics computational analysis were used study inhibition by analogous Kojic acid. The main interactions occurring...

Fusarium disease causes considerable losses in the cultivation of Piper nigrum, black pepper used culinary world. Brazil was largest producer pepper, but recent years has lost this hegemony, with a significant reduction its production, due to ravages produced by solani f. sp. piperis, fungus which disease. Scientific research seeks new alternatives for control and existence other species Brazilian Amazon, resistant disease, are being considered context. The main constituents oil divaricatum...

Reversible and irreversible covalent ligands are advanced cysteine protease inhibitors in the drug development pipeline. K777 is an inhibitor of cruzain, a necessary enzyme for survival Trypanosoma cruzi (T. cruzi) parasite, causative agent Chagas disease. Despite their importance, still often avoided due to risk adverse effects. Herein, we replaced vinyl sulfone group with nitrile moiety obtain reversible (Neq0682) protease. Then, used experimental computational techniques explore details...

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using combination drug repositioning and rigorous computational modeling methodologies such as molecular docking dynamics (MD) simulations followed by binding free energy calculations. Six including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin Niclosamide with promising anti-SARS-CoV-2 activity screened in silico against four proteins-papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), main...

Neglected Tropical Diseases often receive insufficient attention and investment from the pharmaceutical industry despite their significant global health burden. Among these diseases, Chagas disease affects approximately 8 million people worldwide, with Trypanosoma cruzi ( T. cruzi) identified as its causative agent. Cruzain (Cz) enzyme plays a critical role in life cycle of serves validated molecular target for developing new therapeutic compounds. This study aimed to identify potential Cz...

Bacterial cell walls contain peptidoglycan (PG), a scaffold that provides proper rigidity to resist lysis from internal osmotic pressure and barrier protect cells against external stressors. It consists of repeating sugar units with linkage stem peptide becomes cross-linked by wall transpeptidases (TP). While synthetic PG fragments containing l-lysine in the third position on are easier access, those meso-diaminopimelic acid (m-DAP) pose severe challenge. Herein, we describe solid phase...

Eugenol is a natural compound with well-known repellent activity. However, its pharmaceutical and cosmetic applications are limited, since this highly volatile thermolabile. Nanoencapsulation provides protection, stability, conservation, controlled release for several compounds. Here, eugenol was included in β-cyclodextrin, the complex characterized through X-ray diffraction analysis (XRD) Fourier-transform infrared spectroscopy (FTIR). Additionally, we used molecular dynamics simulations to...

A primary component of all known bacterial cell walls is the peptidoglycan (PG) layer, which composed repeating units sugars connected to short and unusual peptides. The various steps within PG biosynthesis are targets potent antibiotics as proper assembly essential for cellular growth survival. Synthetic mimics have proven be indispensable tools study structure, growth, remodeling. Yet, a common PG, meso-diaminopimelic acid (m-DAP) at third position stem peptide, remains challenging access...

Tuberculosis is perhaps the most persistent human disease caused by an infections bacterium, Mycobacterium tuberculosis. The L,D-transpeptidase enzyme catalyzes formation of 3 → peptidoglycan cross-links Mtb cell wall and facilitates resistance against classical β-lactams. Herein, experimentally proposed mechanism for LdtMt2 was studied performing QM/MM MD simulations. whole mechanistic process includes two stages: acylation deacylation. During step, steps were observed: first step a...

Tyrosinase (TYR) is a metalloenzyme classified as type-3 copper protein, which involved in the synthesis of melanin through catalytic process beginning with conversion amino acid l-Tyrosine (l-Tyr) to l-3,4-dihydroxyphenylalanine (l-DOPA). It plays an important role mechanism melanogenesis various organisms including mammals, plants, and fungi. Herein, we used combination computational molecular modeling techniques dynamic (MD) simulations linear interaction energy (LIE) model evaluate...

Structural and energetic features explain why some drugs can be repositioned to inhibit M pro from SARS-CoV-2.

Abstract The peptidoglycan biosynthesis pathway plays a vital role in bacterial cells, and facilitates layer formation, fundamental structural component of the cell wall. enzymes this are candidates for antibiotic development, as most do not have mammalian homologues. UDP‐N‐acetylglucosamine (UNAG) enolpyruvyl transferase enzyme (MurA) cytoplasmic step is responsible phosphoenolpyruvate (PEP)–UNAG catalytic reaction, forming UNAG enolpyruvate inorganic phosphate. Reportedly,...

Abstract Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is a key‐enzyme for design of new drugs against Chagas disease. Herein, molecular inhibition mechanism GAPDH involving 1,3‐bisphospho‐ D ‐glyceric acid (1,3‐BPGA) analogs were studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and dynamic simulations. The analysis binding contribution individual residues shows that Lys209, Asp210, Arg212, Thr167, Thr197, Thr199, Ser224, Thr226, Ser247, Arg249, water...

Inhibition of mushroom tyrosinase was observed with synthetic dihydropyrano[3,2-b]chromenediones. Among them, DHPC04 displayed the most potent inhibitory activity a Ki value 4 μm, comparable to reference standard inhibitor kojic acid. A kinetic study suggested that these heterocyclic compounds behave as competitive inhibitors for L-DOPA binding site enzyme. Furthermore, molecular modeling provided important insight into mechanism interactions copper active site.

The inactivation mechanism of LDT enzyme from <italic>M. tuberculosis</italic> by carbapenems is described QM/MM and PMF analysis

The odoriferous principle of Aniba canelilla (H.B.K.) Mez is due 1‐nitro‐2‐phenylethane, the main constituent its essential oil and also responsible for plant's cinnamon scent. This nitroderivative was previously reported by their antioxidant, antinociception, cardiovascular, vasorelaxant properties, now it tested as inhibitor acetylcholinesterase using bioautography on TLC plates. a purified fraction containing 1‐nitro‐2‐phenylethane were analyzed GC ‐ MS . percentage content in after...

The substitution of serine and threonine residues in nucleocytoplasmic proteins with 2-acetamido-2-deoxy-β-d-glucopyranose (O-GlcNAc) is an essential post-translational modification found many multicellular eukaryotes. O-glycoprotein 2-acetamino-2-deoxy-β-d-glucopyranosidase (O-GlcNAcase) hydrolyzes O-GlcNAc from post-translationally modified serine/threonine protein. has been implicated several disease states such as cancer, Alzheimer's disease, type II diabetes. For this paper, a model the...

Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy solvation PCU-lactam lactone models their enantiomers as well the PCU-lactam-NH-EAIS lactone-CO-EAIS corresponding diastereomers complexed with South HIV protease was performed. This will enable...

The catalytic mechanism of SalL chlorinase has been investigated by combining quantum mechanical/molecular mechanical (QM/MM) techniques and umbrella sampling simulations to compute free energy profiles. Our results shed light on the interesting fact that substitution chloride with fluorine in leads a loss halogenase activity. potential mean force based DFTB3/MM analysis shows fluorination corresponds barrier 13.5 kcal·mol–1 higher than chlorination. Additionally, our present molecular...

The single crystal X-ray structure of the extracellular portion L,D-transpeptidase (ex-LdtMt2 – residues 120–408) enzyme was recently reported. It observed that imipenem and meropenem inhibit activity this enzyme, responsible for generating L,D-transpeptide linkages in peptidoglycan layer Mycobacterium tuberculosis. Imipenem is more active isothermal titration calorimetry experiments revealed subjected to an entropy penalty upon binding enzyme. Herein, we report a molecular modeling approach...