SuPepMem: A database of innate immune system peptides and their cell membrane interactions.

Host defense peptides (HDPs) are short cationic peptides that play a key role in the innate immune response of all living organisms. Their action mechanism does not depend on the presence of protein receptors, but on their ability to target and disrupt the membranes of a wide range of pathogenic and pathologic cells which are recognized by their specific compositions, typically with a relatively high concentration of anionic lipids. Lipid profile singularities have been found in cancer, inflammation, bacteria, viral infections, and even in senescent cells, enabling the possibility to use them as therapeutic targets and/or diagnostic biomarkers. Molecular dynamics (MD) simulations are extraordinarily well suited to explore how HDPs interact with membrane models, providing a large amount of qualitative and quantitative information that, nowadays, cannot be assessed by wet-lab methods at the same level of temporal and spatial resolution. Here, we present SuPepMem, an open-access repository containing MD simulations of different natural and artificial peptides with potential membrane lysis activity, interacting with membrane models of healthy mammal, bacteria, viruses, cancer or senescent cells. In addition to a description of the HDPs and the target systems, SuPepMem provides both the input files necessary to run the simulations and also the results of some selected analyses, including structural and MD-based quantitative descriptors. These descriptors are expected to be useful to train machine learning algorithms that could contribute to design new therapeutic peptides. Tools for comparative analysis between different HDPs and model membranes, as well as to restrict the queries to structural and time-averaged properties are also available. SuPepMem is a living project, that will continuously grow with more simulations including peptides of different sequences, MD simulations with different number of peptide units, more membrane models and also several resolution levels. The database is open to MD simulations from other users (after quality check by the SuPepMem team). SuPepMem is freely available under https://supepmem.com/.

Crystal, spectroscopic and quantum mechanics studies of Schiff bases derived from 4-nitrocinnamaldehyde.

Two Schiff bases, (E)-1-(4-methoxyphenyl)-N-((E)-3-(4-nitrophenyl)allylidene)methanamine (compound 1) and (E)-N-((E)-3-(4-nitrophenyl)allylidene)-2-phenylethanamine (compound 2) have been synthesized and characterized using spectroscopic methods; time of flight MS, 1H and 13C NMR, FT-IR, UV-VIS, photoluminescence and crystallographic methods. The structural and electronic properties of compounds 1 and 2 in the ground state were also examined using the DFT/B3LYP functional and 6-31 + G(d,p) basis set, while the electronic transitions for excited state calculations were carried out using the TD-DFT/6-31 + G(d,p) method. The Schiff base compounds, 1 and 2 crystallized in a monoclinic crystal system and the P21/c space group. The emission spectra of the compounds are attributed to conjugated π-bond interaction while the influence of the intra-ligand charge transfer resulted in a broad shoulder for 1 and a double emission peak for 2. The calculated transitions at 450 and 369 nm for 1 and 2 respectively are in reasonable agreement with the experimental results. The higher values of dipole moment, linear polarizability and first hyperpolarizability of 1, suggest a better optical property and better candidate for the development of nonlinear optical (NLO) materials.

Exploring the bioactivity of pentacyclic triterpenoids as potential antimycobacterial nutraceutics: Insights through comparative biomolecular modelling.

A group of bioactive compounds known as triterpenoids, which are often found in plant materials, have been tested to possess nutritional and pharmaceutical activity. These plant components are referred to as nutraceuticals, and are used as therapeutic agents. In this study, we explore the interactions of betulinic acid (BA), oleanolic acid (OA), ursolic acid (UA), and maslinic acid (MA) against FadA5. Studies have identified FadA5, a trifunctional enzyme-like thiolase, as a target towards Mycobacterium tuberculosis inhibition. The investigation involves molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) applications. Analyses of the four pentacyclic triterpenoids binding to FadA5 showed appreciable bioactivity against FadA5. The application of two or more theoretical models to unravel ligand-enzyme binding energies can pave the way for accurate binding affinity prediction and validation.

Density functional theory study of gold(III)-dithiocarbamate complexes with characteristic anticancer potentials.

The application of gold as drug candidate dated back to 2500 BC and its relevance in medicine became more appealing following 1985 FDA approval of ingested Auranofin for the treatment of rheumatoid arthritis. In this study, we have provided a density functional theory (DFT) study of some gold(III)-dithiocarbamate complexes with characteristic anticancer potentials. DFT calculation of the reactivity and selectivity properties of these complexes with an enzyme template of thioredoxin reductase (TrxR) was carried out. The investigation proceeds with theoretical characterization of the selected compounds through spectroscopic analyses. IR and UV-vis analyses were carried out and the calculated values are comparable to experimental results. NMR assignment was determined for the gold compounds and the estimated theoretical chemical shift values agree with available experimental data from literature. The obtained DFT-based chemical parameters proved to be significant in evaluating the selectivity, reactivity and stability of the gold(III) complexes as potential anticancer moieties, specifically against TrxR. Calculated binding free energy gave similar order with the available in vitro inhibition profile of these gold(III)-dithiocarbamate complexes against TrxR. The outcome of this DFT study could serve as a useful guide towards future design of new and potent anticancer drug candidate. The investigated chemical reactivity properties could be considered and applied to a wide range of bioactive compounds and enzyme-inhibitor systems.

Synthesis and structures of divalent Co, Ni, Zn and Cd complexes of mixed dichalcogen and dipnictogen ligands with corrosion inhibition properties: experimental and computational studies.

The structural and corrosion inhibition properties of four different transition-metal complexes of heteroleptic S-donor atom dithiophosphonate and N-donor atom phenanthroline ligands are reported. Full structural characterization of the Co, Ni, Zn and Cd complexes was achieved with the aid of single-crystal X-ray crystallography. Structural elucidation revealed the formation of a 4-coordinate Zn(ii) complex, and 6-coordinate Ni(ii) and Cd(ii), as well as a novel dithiophosphonato Co(ii) complex. The ability of the complexes with this ligand type to act as inhibitors of mild steel corrosion in 1 M HCl solution is reported for the first time. Corrosion inhibition potentials of the complexes were assessed using potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and density functional theory (DFT). The open circuit potential (OCP) time profile showed the system achieved a steady-state potential before the first 600 s after submerging the working electrode in the corrosive medium. The studied metal complexes are good inhibitors of mild steel corrosion in 1 M HCl and were found to retard the corrosion rate by forming an adsorbed pseudocapacitive film on the steel surface. The order of inhibition efficiencies was in the order Ni (94.14%) > Cd (92.28%) > Zn (91.14%) > Co (72.53%).

Structure and Function of L,D- and D,D-Transpeptidase Family Enzymes from Mycobacterium tuberculosis.

Peptidoglycan, the exoskeleton of bacterial cell and an essential barrier that protects the cell, is synthesized by a pathway where the final steps are catalysed by transpeptidases. Knowledge of the structure and function of these vital enzymes that generate this macromolecule in M. tuberculosis could facilitate the development of potent lead compounds against tuberculosis. This review summarizes the experimental and computational studies to date on these aspects of transpeptidases in M. tuberculosis that have been identified and validated. The reported structures of L,D- and D,D-transpeptidases, as well as their functionalities, are reviewed and the proposed enzymatic mechanisms for L,D-transpeptidases are summarized. In addition, we provide bioactivities of known tuberculosis drugs against these enzymes based on both experimental and computational approaches. Advancing knowledge about these prominent targets supports the development of new drugs with novel inhibition mechanisms overcoming the current need for new drugs against tuberculosis.

Identification of potent L,D-transpeptidase 5 inhibitors for Mycobacterium tuberculosis as potential anti-TB leads: virtual screening and molecular dynamics simulations.

Virtual screening is a useful in silico approach to identify potential leads against various targets. It is known that carbapenems (doripenem and faropenem) do not show any reasonable inhibitory activities against L,D-transpeptidase 5 (LdtMt5) and also an adduct of meropenem exhibited slow acylation. Since these drugs are active against L,D-transpeptidase 2 (LdtMt2), understanding the differences between these two enzymes is essential. In this study, a ligand-based virtual screening of 12,766 compounds followed by molecular dynamics (MD) simulations was applied to identify potential leads against LdtMt5. To further validate the obtained virtual screening ranking for LdtMt5, we screened the same libraries of compounds against LdtMt2 which had more experimetal and calculated binding energies reported. The observed consistency between the binding affinities of LdtMt2 validates the obtained virtual screening binding scores for LdtMt5. We subjected 37 compounds with docking scores ranging from - 7.2 to - 9.9 kcal mol-1 obtained from virtual screening for further MD analysis. A set of compounds (n = 12) from four antibiotic classes with ≤ - 30 kcal mol-1 molecular mechanics/generalized born surface area (MM-GBSA) binding free energies (ΔGbind) was characterized. A final set of that, all ß-lactams (n = 4), was considered. The outcome of this study provides insight into the design of potential novel leads for LdtMt5. Graphical abstract.

The Driving Force for the Acylation of ß-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study.

ß-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the ß-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C-N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of ß-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C-N), which is why the six-membered ring lactams C-N bond are more rigid than those with five-membered ring lactams. The calculated ΔG# values from the acylation reaction of the lactams (involving the S-H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives (17.58 kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the ß-lactam ring, than ring strain.

Inhibition mechanism of L,D-transpeptidase 5 in presence of the ß-lactams using ONIOM method.

Tuberculosis (TB) is one of the world's deadliest diseases resulting from infection by the bacterium, Mycobacterium tuberculosis (M.tb). The L,D-transpeptidase enzymes catalyze the synthesis of 3 → 3 transpeptide linkages which are predominant in the peptidoglycan of the M.tb cell wall. Carbapenems is class of ß-lactams that inactivate L,D-transpeptidases by acylation, although differences in antibiotic side chains modulate drug binding and acylation rates. Herein, we used a two-layered our Own N-layer integrated Molecular Mechanics ONIOM method to investigate the catalytic mechanism of L,D-transpeptidase 5 (LdtMt5) by ß-lactam derivatives. LdtMt5 complexes with six ß-lactams, ZINC03788344 (1), ZINC02462884 (2), ZINC03791246 (3), ZINC03808351 (4), ZINC03784242 (5) and ZINC02475683 (6) were simulated. The QM region (high-level) comprises the ß-lactam, one water molecule and the Cys360 catalytic residue, while the rest of the LdtMt5 residues were treated with AMBER force field. The activation energies (ΔG#) were calculated with B3LYP, M06-2X and ωB97X density functionals with 6-311++G(2d, 2p) basis set. The ΔG# for the acylation of LdtMt5 by the selected ß-lactams were obtained as 13.67, 20.90, 22.88, 24.29, 27.86 and 28.26 kcal mol-1respectively. Several of the compounds showed an improved ΔG# when compared to the previously calculated energies for imipenem and meropenem for the acylation step for LdtMt5. This model provides further validation of the catalytic inhibition mechanism of LDTs with atomistic detail.

The catalytic role of water in the binding site of l,d-transpeptidase 2 within acylation mechanism: A QM/MM (ONIOM) modelling.

Mycobacterium tuberculosis is the causative agent of Tuberculosis. Formation of 3 → 3 crosslinks in the peptidoglycan layer of M. tuberculosis is catalyzed by l,d-transpeptidases. These enzymes can confer resistance against classical ß-lactams that inhibit enzymes that generate 4 → 3 peptidoglycan crosslinks. The focus of this study is to investigate the catalytic role of water molecules in the acylation mechanism of the ß-lactam ring within two models; 4- and 6-membered ring systems using two-layered our Own N-layer integrated Molecular Mechanics ONIOM (B3LYP/6-311++G(2d,2p): AMBER) model. The obtained thermochemical parameters revealed that the 6-membered ring model best describes the inhibition mechanism of acylation which indicates the role of water in the preference of 6-membered ring reaction pathway. This finding is in accordance with experimental data for the rate-limiting step of cysteine protease with the same class of inhibitor and binding affinity for both inhibitors. As expected, the ΔG# results also reveal that the 6-membered ring reaction pathway is the most favourable. The electrostatic potential (ESP) and the natural bond orbital analysis (NBO) showed stronger interactions in 6-membered ring transition state (TS-6) mechanism involving water in the active site of the enzyme. This study could be helpful in the development of novel antibiotics against l,d-transpeptidase.