The purpose of this quick guide is to help new modelers who have little or no background in comparative modeling yet are keen to produce high-resolution protein 3D structures for their study by following systematic good modeling practices, using affordable personal computers or online computational resources. Through the available experimental 3D-structure repositories, the modeler should be able to access and use the atomic coordinates for building homology models. We also aim to provide the modeler with a rationale behind making a simple list of atomic coordinates suitable for computational analysis abiding to principles of physics (e.g., molecular mechanics). Keeping that objective in mind, these quick tips cover the process of homology modeling and some postmodeling computations such as molecular docking and molecular dynamics (MD). A brief section was left for modeling nonprotein molecules, and a short case study of homology modeling is discussed.
- MeSH
- Algorithms MeSH
- Amino Acids chemistry MeSH
- Models, Biological MeSH
- Databases, Protein MeSH
- Internet MeSH
- Ions MeSH
- Hydrogen-Ion Concentration MeSH
- Ligands MeSH
- Computer Simulation MeSH
- Protein Processing, Post-Translational MeSH
- Proteins chemistry MeSH
- Solvents MeSH
- Protein Folding MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Software MeSH
- Machine Learning MeSH
- Structural Homology, Protein MeSH
- Water MeSH
- Computational Biology methods MeSH
- Imaging, Three-Dimensional methods MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The acid dissociation constant is an important molecular property, and it can be successfully predicted by Quantitative Structure-Property Relationship (QSPR) models, even for in silico designed molecules. We analyzed how the methodology of in silico 3D structure preparation influences the quality of QSPR models. Specifically, we evaluated and compared QSPR models based on six different 3D structure sources (DTP NCI, Pubchem, Balloon, Frog2, OpenBabel, and RDKit) combined with four different types of optimization. These analyses were performed for three classes of molecules (phenols, carboxylic acids, anilines), and the QSPR model descriptors were quantum mechanical (QM) and empirical partial atomic charges. Specifically, we developed 516 QSPR models and afterward systematically analyzed the influence of the 3D structure source and other factors on their quality. Our results confirmed that QSPR models based on partial atomic charges are able to predict pKa with high accuracy. We also confirmed that ab initio and semiempirical QM charges provide very accurate QSPR models and using empirical charges based on electronegativity equalization is also acceptable, as well as advantageous, because their calculation is very fast. On the other hand, Gasteiger-Marsili empirical charges are not applicable for pKa prediction. We later found that QSPR models for some classes of molecules (carboxylic acids) are less accurate. In this context, we compared the influence of different 3D structure sources. We found that an appropriate selection of 3D structure source and optimization method is essential for the successful QSPR modeling of pKa. Specifically, the 3D structures from the DTP NCI and Pubchem databases performed the best, as they provided very accurate QSPR models for all the tested molecular classes and charge calculation approaches, and they do not require optimization. Also, Frog2 performed very well. Other 3D structure sources can also be used but are not so robust, and an unfortunate combination of molecular class and charge calculation approach can produce weak QSPR models. Additionally, these 3D structures generally need optimization in order to produce good quality QSPR models.
- MeSH
- Chemical Phenomena * MeSH
- Quantitative Structure-Activity Relationship * MeSH
- Quantum Theory MeSH
- Molecular Conformation * MeSH
- Models, Molecular * MeSH
- Computer Simulation MeSH
- Drug Design MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- Folic Acid Antagonists chemistry pharmacology MeSH
- Tetrahydrofolate Dehydrogenase chemistry MeSH
- Quantitative Structure-Activity Relationship MeSH
- Molecular Conformation MeSH
- Models, Molecular * MeSH
- Molecular Structure MeSH
- Drug Discovery MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Protein Binding MeSH
- Hydrogen Bonding MeSH
- Yersinia pestis drug effects enzymology MeSH
- Publication type
- Letter MeSH
A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Butyrylcholinesterase blood metabolism MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Electrophorus MeSH
- Indans chemistry pharmacology MeSH
- Horses MeSH
- Quantitative Structure-Activity Relationship * MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Piperidines chemistry pharmacology MeSH
- Recombinant Proteins metabolism MeSH
- Tacrine analogs & derivatives chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
We describe a novel approach of reaction representation as a combination of two mixtures: a mixture of reactants and a mixture of products. In turn, each mixture can be encoded using an earlier reported approach involving simplex descriptors (SiRMS). The feature vector representing these two mixtures results from either concatenated product and reactant descriptors or the difference between descriptors of products and reactants. This reaction representation doesn't need an explicit labeling of a reaction center. The rigorous "product-out" cross-validation (CV) strategy has been suggested. Unlike the naïve "reaction-out" CV approach based on a random selection of items, the proposed one provides with more realistic estimation of prediction accuracy for reactions resulting in novel products. The new methodology has been applied to model rate constants of E2 reactions. It has been demonstrated that the use of the fragment control domain applicability approach significantly increases prediction accuracy of the models. The models obtained with new "mixture" approach performed better than those required either explicit (Condensed Graph of Reaction) or implicit (reaction fingerprints) reaction center labeling.
In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
- MeSH
- Anti-Bacterial Agents chemistry pharmacology toxicity MeSH
- Bacteria drug effects MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Fungi drug effects MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Cricetinae MeSH
- Quantitative Structure-Activity Relationship * MeSH
- Molecular Conformation MeSH
- Pyridines chemistry pharmacology toxicity MeSH
- Molecular Dynamics Simulation * MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Cricetinae MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
sv.
- MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Molecular Sequence Data MeSH
- Molecular Structure MeSH
- Protein Binding MeSH
- Publication type
- Periodical MeSH
- Conspectus
- Biochemie. Molekulární biologie. Biofyzika
- NML Fields
- biologie
- biochemie
Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate determining step in the generation of Aβ peptide and is widely considered as a potential therapeutic drug target for Alzheimer's disease (AD). Active site of BACE1 contains catalytic aspartic (Asp) dyad and flap. Asp dyad cleaves the substrate amyloid precursor protein with the help of flap. Currently, there are no marketed drugs available against BACE1 and existing inhibitors are mostly pseudopeptide or synthetic derivatives. There is a need to search for a potent inhibitor with natural scaffold interacting with flap and Asp dyad. This study screens the natural database InterBioScreen, followed by three-dimensional (3D) QSAR pharmacophore modeling, mapping, in silico ADME/T predictions to find the potential BACE1 inhibitors. Further, molecular dynamics of selected inhibitors were performed to observe the dynamic structure of protein after ligand binding. All conformations and the residues of binding region were stable but the flap adopted a closed conformation after binding with the ligand. Bond oligosaccharide interacted with the flap as well as catalytic dyad via hydrogen bond throughout the simulation. This led to stabilize the flap in closed conformation and restricted the entry of substrate. Carbohydrates have been earlier used in the treatment of AD because of their low toxicity, high efficiency, good biocompatibility, and easy permeability through the blood-brain barrier. Our finding will be helpful in identify the potential leads to design novel BACE1 inhibitors for AD therapy.
- MeSH
- Algorithms MeSH
- Aspartic Acid Endopeptidases antagonists & inhibitors metabolism MeSH
- Biological Products chemistry pharmacology MeSH
- Enoxaparin pharmacology MeSH
- Heparitin Sulfate pharmacology MeSH
- Inhibitory Concentration 50 MeSH
- Enzyme Inhibitors chemistry pharmacology MeSH
- Crystallography, X-Ray MeSH
- Quantitative Structure-Activity Relationship * MeSH
- Humans MeSH
- Ligands MeSH
- Oligosaccharides chemistry MeSH
- Drug Evaluation, Preclinical * MeSH
- Amyloid Precursor Protein Secretases antagonists & inhibitors metabolism MeSH
- Molecular Dynamics Simulation * MeSH
- Hydrogen Bonding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
From four molecules, inspired by the structural features of fascaplysin, with an interesting potential to inhibit cyclin-dependent kinases (CDKs), we designed a new series of tri-heterocyclic derivatives based on 1H-pyrrolo[2,3-b]pyridine (7-azaindole) and triazole heterocycles. Using a Huisgen type [3 + 2] cycloaddition as the convergent key step, 24 derivatives were synthesized and their biological activities were evaluated. Comparative molecular field analysis (CoMFA), based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, was conducted on a series of 30 compounds from the literature with high to low known inhibitory activity towards CDK2/cyclin E and was validated by a test set of 5 compounds giving satisfactory predictive r(2) value of 0.92. Remarkably, it also gave a good prediction of pIC50 for our tri-heterocyclic series which reinforce the validation of this model for the pIC50 prediction of external set compounds. The most promising compound, 43, showed a micro-molar range inhibitory activity against CDK2/cyclin E and also an antiproliferative and proapoptotic activity against a panel of cancer cell lines.
- MeSH
- Cyclin E antagonists & inhibitors metabolism MeSH
- Cyclin-Dependent Kinase 2 antagonists & inhibitors metabolism MeSH
- Heterocyclic Compounds chemical synthesis chemistry pharmacology MeSH
- Indoles chemical synthesis chemistry pharmacology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Quantitative Structure-Activity Relationship MeSH
- Humans MeSH
- Models, Molecular * MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated.
