Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.
- MeSH
- Algorithms MeSH
- Chemistry, Pharmaceutical MeSH
- Quantum Theory MeSH
- Humans MeSH
- AMP-Activated Protein Kinases metabolism chemistry MeSH
- Molecular Dynamics Simulation * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 μg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 μM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.
- MeSH
- Antitubercular Agents pharmacology chemistry MeSH
- Bacterial Proteins metabolism MeSH
- Quinolines * pharmacology MeSH
- Isatin * pharmacology MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis * MeSH
- Oxidoreductases metabolism MeSH
- Acyl Carrier Protein pharmacology MeSH
- Molecular Docking Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox. MATERIAL AND METHOD: Preliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc. RESULTS: The mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system. CONCLUSION: In conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.
- MeSH
- Antiviral Agents pharmacology MeSH
- COVID-19 * MeSH
- Curcumin * pharmacology MeSH
- Humans MeSH
- Drug Discovery MeSH
- Mpox, Monkeypox * MeSH
- Smallpox * drug therapy MeSH
- Drug Design MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Variola virus * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
SARS-CoV-2 cause fatal infection in 213 countries accounting for the death of millions of people globally. In the present study, phytochemicals from spices were assessed for their ability to interact with SARS-CoV-2 MPro. Structure based virtual screening was performed with 146 phytochemicals from spices using Autodock Vina. Phytochemicals with binding energy ≥ -8.0 kcal/mol were selected to understand their interaction with MPro. Virtual screening was further validated by performing molecular docking to generate favorable docked poses and the participation of important amino acid residues. Molecular dynamics simulation for the docked poses was performed to study thermodynamic properties of the protein, ligand and protein-ligand complexes. The finding shows that cinnamtannin B2 and cyanin showed favorable binding affinity values with SARS-CoV-2 MPro. The results are comparable in terms of docked poses, important amino acid participation and thermodynamic properties with the standard control drugs remdesivir, benazepril and hydroxychloroquine diphosphate. Prime MM-GBSA was employed for end-point binding energy calculation. Binding to domain I and II of MPro were mediated through the OH, SH, NH2 and non-polar side chain of amino acids. Cinnamtannin B2 and cyanin binds to MPro with many sub sites within the active site with RMSD and RMSF within 4 Å. The results computed using Prime MM-GBSA show that cinnamtannin B2 (-68.54940214 kcal/mol) and cyanin (-62.1902835 kcal/mol) have better binding affinity in comparison to hydroxychloroquine diphosphate (-54.00912412 kcal/mol) and benazepril (-53.70242369 kcal/mol). The results provide a basis for exploiting cinnamtannin B2 and cyanin as a starting point potential candidate for the development of drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
BACKGROUND AND OBJECTIVE: Large deformations in synthetic meshes used in pelvic organ prolapse surgery may lead to suboptimal support for the underlying tissue, graft-related complications as well as recurrence. Our aim was to quantify in vivo longitudinal changes in mesh shape and geometry in a large animal model. We compare two commonly used mesh shapes, armed and flat, that are differently affixed. The secondary outcomes were active and passive biomechanical properties. METHODS: A total of 18 animals were used. Six each were implanted with either an arm mesh, a flat mesh or underwent a sham surgery. PVDF meshes loaded with Fe2O3were used to facilitate their visualization in vivo. MR images were taken at 2, 14 and 60 days after implantation and 3D models of the meshes were created at each time point. We calculate the Effective Surface Area (ESA), i.e. the support that the mesh provides to the underlying tissue using custom developed techniques. Longitudinal changes in the mesh shape were studied by comparing the respective 3D models using part comparison analyses. The root means square difference (RMSD) and the modified Hausdorff distance (MHD) were calculated to obtain an objective value for the part comparisons. Wall thickness maps were produced on 3D models. Mesh arm length and their ellipticity profiles were also evaluated. Active and passive biomechanical tests on vaginal tissue overlaying the mesh were conducted using a contractility assay and a uniaxial loading protocol. RESULTS: MR images of 5 animals in each group were used for longitudinal comparison. Compared to the initial implant size, there was an immediate drop in the ESA measurement at day 2 of almost 32.22 [7.06] % (median [IQR]) for flat meshes, and by 17.59 [6.50] % for arm meshes. After 14 days, the reduction in area was 41.84 [14.89] % and 27.18 [20.44] %, and at day 60 it was 36.61 [6.64] % and 26.43 [14.56] % for the flat and armed meshes respectively. The reduction in area in the two groups was different between the two groups only day 14 (p = 0.046). The ellipticity of the arms was 0.81 [0.08] (median [IQR]) and there was no significant change in the ellipticity profiles over time. The mesh arm length did not change significantly over time. The part comparison showed a maximum difference of 4.26 [3.29] mm in 3D models according to the MHD measure, which is clinically not relevant. Comparison of high thickness areas on the thickness maps correlated well with the areas of mesh folding in the arm mesh group observed during postmortem dissection. Thickness maps did not help us understand why the flat meshes had a reduction in support area. The comfort zone stiffness of the flat mesh and of the central part of the arm mesh were 2.4 fold and 4.5 times stiffer compared to sham groups, respectively. The arms were 36% stiffer than the central part of the mesh. The comfort zone length of the sham group was 46% longer than the flat mesh group (p = 0.027) and 59% longer than that of the central part of the arm mesh (p = 0.005). There was no significant difference in vaginal contractile forces generated in samples from the arm, flat mesh, and sham groups. CONCLUSIONS: This is a first longitudinal study observing deformations in vaginally implanted synthetic meshes in a large animal model. A novel methodology is presented to calculate the area of the vaginal tissue effectively supported by the mesh implant. Immediately post-operatively, a reduction in 32% and 17% was noted, which remained stable over the 60 following days of observation. We use thickness maps to analyze the cause of this dramatic immediate reduction. In the armed mesh we found it to be mesh folding at the interface between the arms and central part. For the flat mesh we suggest that pore aggregation during suturing.
- MeSH
- Surgical Mesh * MeSH
- Longitudinal Studies MeSH
- Magnetic Resonance Imaging * MeSH
- Sheep MeSH
- Pelvic Organ Prolapse surgery MeSH
- Materials Testing * MeSH
- Vagina surgery MeSH
- Ferric Compounds MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
G protein-coupled receptors (GPCRs) are hard to crystallize. However, attempts to predict their structure have boomed as a result of advancements in crystallographic techniques. This trend has allowed computer-aided molecular modeling of GPCRs. We analyzed the performance of four molecular modeling programs in pose evaluation of re-docked antagonists / inverse agonists to 11 original crystal structures of aminergic GPCRs using an induced fit-docking procedure. AutoDock and Glide were used for docking. AutoDock binding energy function, GlideXP, Prime MM-GB/SA, and YASARA binding function were used for pose scoring. Root mean square deviation (RMSD) of the best pose ranged from 0.09 to 1.58 Å, and median RMSD of the top 60 poses ranged from 1.47 to 3.83 Å. However, RMSD of the top pose ranged from 0.13 to 7.33 Å and ranking of the best pose ranged from the 1st to 60th out of 60 poses. Moreover, analysis of ligand-receptor interactions of top poses revealed substantial differences from interactions found in crystallographic structures. Bad ranking of top poses and discrepancies between top docked poses and crystal structures render current simple docking methods unsuitable for predictive modeling of receptor-ligand interactions. Prime MM-GB/SA optimized for 3NY9 by multiple linear regression did not work well at 3NY8 and 3NYA, structures of the same receptor with different ligands. However, 9 of 11 trajectories of molecular dynamics simulations by Desmond of top poses converged with trajectories of crystal structures. Key interactions were properly detected for all structures. This procedure also worked well for cross-docking of tested β2-adrenergic antagonists. Thus, this procedure represents a possible way to predict interactions of antagonists with aminergic GPCRs.
The extrinsic proteins of photosystem II of higher plants and green algae PsbO, PsbP, PsbQ, and PsbR are essential for stable oxygen production in the oxygen evolving center. In the available X-ray crystallographic structure of higher plant PsbQ residues S14-Y33 are missing. Building on the backbone NMR assignment of PsbQ, which includes this "missing link", we report the extended resonance assignment including side chain atoms. Based on nuclear Overhauser effect spectra a high resolution solution structure of PsbQ with a backbone RMSD of 0.81 Å was obtained from torsion angle dynamics. Within the N-terminal residues 1-45 the solution structure deviates significantly from the X-ray crystallographic one, while the four-helix bundle core found previously is confirmed. A short α-helix is observed in the solution structure at the location where a β-strand had been proposed in the earlier crystallographic study. NMR relaxation data and unrestrained molecular dynamics simulations corroborate that the N-terminal region behaves as a flexible tail with a persistent short local helical secondary structure, while no indications of forming a β-strand are found.
- MeSH
- Photosystem II Protein Complex chemistry genetics metabolism MeSH
- Crystallography, X-Ray MeSH
- Magnetic Resonance Spectroscopy methods MeSH
- Recombinant Proteins chemistry metabolism MeSH
- Plant Proteins chemistry genetics metabolism MeSH
- Solutions MeSH
- Protein Structure, Secondary * MeSH
- Amino Acid Sequence MeSH
- Molecular Dynamics Simulation * MeSH
- Spinacia oleracea genetics metabolism MeSH
- Protein Structure, Tertiary MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
We focused on the parametrization and evaluation of empirical models for fast and accurate calculation of conformationally dependent atomic charges in proteins. The models were based on the electronegativity equalization method (EEM), and the parametrization procedure was tailored to proteins. We used large protein fragments as reference structures and fitted the EEM model parameters using atomic charges computed by three population analyses (Mulliken, Natural, iterative Hirshfeld), at the Hartree-Fock level with two basis sets (6-31G*, 6-31G**) and in two environments (gas phase, implicit solvation). We parametrized and successfully validated 24 EEM models. When tested on insulin and ubiquitin, all models reproduced quantum mechanics level charges well and were consistent with respect to population analysis and basis set. Specifically, the models showed on average a correlation of 0.961, RMSD 0.097 e, and average absolute error per atom 0.072 e. The EEM models can be used with the freely available EEM implementation EEM_SOLVER.
- MeSH
- Time Factors MeSH
- Models, Chemical * MeSH
- Databases, Protein MeSH
- Insulin chemistry MeSH
- Protein Conformation MeSH
- Quantum Theory MeSH
- Humans MeSH
- Peptide Fragments chemistry MeSH
- Gases MeSH
- Computer Simulation MeSH
- Solutions MeSH
- Sensitivity and Specificity MeSH
- Software * MeSH
- Static Electricity MeSH
- Ubiquitin chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Twelve homology models of the human M2 muscarinic receptor using different sets of templates have been designed using the Prime program or the modeller program and compared to crystallographic structure (PDB:3UON). The best models were obtained using single template of the closest published structure, the M3 muscarinic receptor (PDB:4DAJ). Adding more (structurally distant) templates led to worse models. Data document a key role of the template in homology modeling. The models differ substantially. The quality checks built into the programs do not correlate with the RMSDs to the crystallographic structure and cannot be used to select the best model. Re-docking of the antagonists present in crystallographic structure and relative binding energy estimation by calculating MM/GBSA in Prime and the binding energy function in YASARA suggested it could be possible to evaluate the quality of the orthosteric binding site based on the prediction of relative binding energies. Although estimation of relative binding energies distinguishes between relatively good and bad models it does not indicate the best one. On the other hand, visual inspection of the models for known features and knowledge-based analysis of the intramolecular interactions allows an experimenter to select overall best models manually.
- MeSH
- Protein Conformation * MeSH
- Crystallography, X-Ray * MeSH
- Humans MeSH
- Models, Molecular MeSH
- Receptor, Muscarinic M2 chemistry MeSH
- Amino Acid Sequence MeSH
- Sequence Homology, Amino Acid MeSH
- Molecular Docking Simulation MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
There is a paramount need to develop new techniques and tools that will extract as much information as possible from the ever growing repository of protein 3D structures. We report here on the development of a software tool for the multiple superimposition of large sets of protein structural motifs. Our superimposition methodology performs a systematic search for the atom pairing that provides the best fit. During this search, the RMSD values for all chemically relevant pairings are calculated by quaternion algebra. The number of evaluated pairings is markedly decreased by using PDB annotations for atoms. This approach guarantees that the best fit will be found and can be applied even when sequence similarity is low or does not exist at all. We have implemented this methodology in the Web application SiteBinder, which is able to process up to thousands of protein structural motifs in a very short time, and which provides an intuitive and user-friendly interface. Our benchmarking analysis has shown the robustness, efficiency, and versatility of our methodology and its implementation by the successful superimposition of 1000 experimentally determined structures for each of 32 eukaryotic linear motifs. We also demonstrate the applicability of SiteBinder using three case studies. We first compared the structures of 61 PA-IIL sugar binding sites containing nine different sugars, and we found that the sugar binding sites of PA-IIL and its mutants have a conserved structure despite their binding different sugars. We then superimposed over 300 zinc finger central motifs and revealed that the molecular structure in the vicinity of the Zn atom is highly conserved. Finally, we superimposed 12 BH3 domains from pro-apoptotic proteins. Our findings come to support the hypothesis that there is a structural basis for the functional segregation of BH3-only proteins into activators and enablers.
