LDH-Indomethacin Nanoparticles Antitumoral Action: A Possible Coadjuvant Drug for Cancer Therapy.

Indomethacin (INDO) has a mechanism of action based on inhibiting fatty acids cyclooxygenase activity within the inflammation process. The action mechanism could be correlated with possible anticancer activity, but its high toxicity in normal tissues has made therapy difficult. By the coprecipitation method, the drug carried in a layered double hydroxides (LDH) hybrid matrix would reduce its undesired effects by promoting chemotherapeutic redirection.

Role of UDP-N-acetylmuramic acid in the regulation of MurA activity revealed by molecular dynamics simulations.

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

Assessment of host-guest molecular encapsulation of eugenol using β-cyclodextrin.

Eugenol is a natural compound with well-known repellent activity. However, its pharmaceutical and cosmetic applications are limited, since this compound is highly volatile and thermolabile. Nanoencapsulation provides protection, stability, conservation, and controlled release for several compounds.

Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations.

Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an equal to 0.

Computational Analysis of SAM Analogs as Methyltransferase Inhibitors of nsp16/nsp10 Complex from SARS-CoV-2.

Methyltransferases (MTases) enzymes, responsible for RNA capping into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are emerging important targets for the design of new anti-SARS-CoV-2 agents. Here, analogs of S-adenosylmethionine (SAM), obtained from the bioisosteric substitution of the sulfonium and amino acid groups, were evaluated by rigorous computational modeling techniques such as molecular dynamics (MD) simulations followed by relative binding free analysis against nsp16/nsp10 complex from SARS-CoV-2. The most potent inhibitor () shows the lowest binding free energy (-58.

In Silico Study towards Repositioning of FDA-Approved Drug Candidates for Anticoronaviral Therapy: Molecular Docking, Molecular Dynamics and Binding Free Energy Calculations.

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins-papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)-in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors.

Novel Azine Linked Hybrids of 2-Indolinone and Thiazolodinone Scaffolds as CDK2 Inhibitors with Potential Anticancer Activity: In Silico Design, Synthesis, Biological, Molecular Dynamics and Binding Free Energy Studies.

Molecular hybrid of 2-indolinone-thiazolidinone is a well known scaffold for variable biological activities including anticancer activity. Accordingly, in the current work aided with structure-based molecular modeling studies, a library of novel twenty-six hybrids, 4(a-z), was designed and synthesized. Docking studies in the active site of CDK2, one of the key checkpoints enzymes, revealed that the binding scores of the designed molecules are comparable to the reference enzyme's inhibitors Sunitinib, Nintedanib, and Semaxanib.

Drug repurposing and computational modeling for discovery of inhibitors of the main protease (M) of SARS-CoV-2.

The main protease (M or 3CL) is a conserved cysteine protease from the coronaviruses and started to be considered an important drug target for developing antivirals, as it produced a deadly outbreak of COVID-19. Herein, we used a combination of drug reposition and computational modeling approaches including molecular docking, molecular dynamics (MD) simulations, and the calculated binding free energy to evaluate a set of drugs in complex with the M enzyme. Particularly, our results show that darunavir and triptorelin drugs have favorable binding free energy (-63.

Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach.

The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication since it protects the virus from host innate immune restriction. In particular, nonstructural protein 16 (nsp16) in complex with nsp10 is a Cap-0 binding enzyme.

QM/MM Study of the Fosfomycin Resistance Mechanism Involving FosB Enzyme.

Multidrug-resistant organisms contain antibiotic-modifying enzymes that facilitate resistance to a variety of antimicrobial compounds. Particularly, the fosfomycin (FOF) drug can be structurally modified by several FOF-modifying enzymes before it reaches the biological target. Among them, FosB is an enzyme that utilizes l-cysteine or bacillithiol in the presence of a divalent metal to open the epoxide ring of FOF and, consequently, inactivate the drug.

Facile Synthesis and Metabolic Incorporation of -DAP Bioisosteres Into Cell Walls of Live Bacteria.

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

Pellucidin A promotes antinociceptive activity by peripheral mechanisms inhibiting COX-2 and NOS: In vivo and in silico study.

Peperomia pellucida (PP) belongs to the Peperomia genus, which has a pantropic distribution. PP is used to treat a wide range of symptoms and diseases, such as pain, inflammation, and hypertension. Intriguingly, PP extract is used by different tropical countries for its anti-inflammatory and antinociceptive effects.

Evaluating the Performance of a Non-Bonded Cu Model Including Jahn-Teller Effect into the Binding of Tyrosinase Inhibitors.

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

Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism.

Reversible and irreversible covalent ligands are advanced cysteine protease inhibitors in the drug development pipeline. is an irreversible inhibitor of cruzain, a necessary enzyme for the survival of the () parasite, the causative agent of Chagas disease. Despite their importance, irreversible covalent inhibitors are still often avoided due to the risk of adverse effects.

Exploring Chloride Selectivity and Halogenase Regioselectivity of the SalL Enzyme through Quantum Mechanical/Molecular Mechanical Modeling.

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 the substitution of chloride with fluorine in SalL chlorinase leads to a loss of halogenase activity. The potential of mean force based on DFTB3/MM analysis shows that fluorination corresponds to a barrier 13.

Mycobacterium abscessus l,d-Transpeptidases Are Susceptible to Inactivation by Carbapenems and Cephalosporins but Not Penicillins.

As a growing number of clinical isolates of are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of are synthesized by nonclassical transpeptidases, namely, the l,d-transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen.

Simulating the inhibition reaction of Mycobacterium tuberculosis L,D-transpeptidase 2 by carbapenems.

A theoretical free energy study describes the inactivation of a new tuberculosis target, the l,d-transpeptidase 2 enzyme. A new reaction mechanism of two carbapenem inhibitors is proposed and their molecular features are determined using QM/MM and PMF approaches. The theoretical findings with the new proposed mechanism agree in principle with the experimental data.

Insights into the mechanism of oxidation of dihydroorotate to orotate catalysed by human class 2 dihydroorotate dehydrogenase: a QM/MM free energy study.

The dihydroorotate dehydrogenase (DHOD) enzyme catalyzes the unique redox reaction in the de novo pyrimidine biosynthesis pathway. In this reaction, the oxidation of dihydroorotate (DHO) to orotate (OA) and reduction of the flavin mononucleotide (FMN) cofactor is catalysed by DHOD. The class 2 DHOD, to which the human enzyme belongs, was experimentally shown to follow a stepwise mechanism but the data did not allow the determination of the order of bond-breaking in a stepwise oxidation of DHO.

Pentacycloundecane lactam vs lactone norstatine type protease HIV inhibitors: binding energy calculations and DFT study.

Background: 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 of less than 1.00 μM.

Targeting the cell wall of Mycobacterium tuberculosis: a molecular modeling investigation of the interaction of imipenem and meropenem with L,D-transpeptidase 2.

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

A QM/MM free energy study of the oxidation mechanism of dihydroorotate dehydrogenase (class 1A) from Lactococcus lactis.

The dihydroorotate dehydrogenase (DHOD) class 1A enzyme catalyzes is the only redox enzyme in the biosynthetic pathway (de novo) of pyrimidines where dihydroorotate (DHO) is oxidized to orotate (OA) coupled to reduction of a flavin mononucleotide (FMN) cofactor. The rupture of two DHO C-H bonds can proceed in a concerted or stepwise way. Herein, the catalytic mechanism of DHOD from Lactococcus lactis involving DHO oxidation (first half-reaction) was described using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach and molecular dynamics simulations.

Antifungal activity and computational study of constituents from Piper divaricatum essential oil against Fusarium infection in black pepper.

Fusarium disease causes considerable losses in the cultivation of Piper nigrum, the black pepper used in the culinary world. Brazil was the largest producer of black pepper, but in recent years has lost this hegemony, with a significant reduction in its production, due to the ravages produced by the Fusarium solani f. sp.

Catalytic mechanism of L,D-transpeptidase 2 from Mycobacterium tuberculosis described by a computational approach: insights for the design of new antibiotics drugs.

Tuberculosis is perhaps the most persistent human disease caused by an infections bacterium, Mycobacterium tuberculosis. The L,D-transpeptidase enzyme catalyzes the formation of 3 → 3 peptidoglycan cross-links of the Mtb cell wall and facilitates resistance against classical β-lactams. Herein, the experimentally proposed mechanism for LdtMt2 was studied by performing QM/MM MD simulations.

Combined kinetic studies and computational analysis on kojic acid analogous as tyrosinase inhibitors.

Tyrosinase is a key enzyme in melanin synthesis and widely distributed in plants and animals tissues. In mammals, this enzyme is related to pigment production, involved in wound healing, primary immune response and it can also contribute to catecholamines synthesis in the brain. Consequently, tyrosinase enzyme represents an attractive and selective target in the field of the medicine, cosmetics and bio-insecticides.