Atomistic molecular dynamics simulations of typical and atypical antipsychotic drugs at the dopamine D2 receptor (D2R) elucidates their inhibition mechanism

<p>Dopamine D2 receptor (D2R) plays a pivotal role in nervous systems. Its dysfunction leads to the schizophrenia, Parkinson’s diseases and drug addiction. Since the crystal structure of the D2R was not solved yet, discovering of potent and highly selective anti-psychotic drugs carry challenges for different neurodegenerative diseases. In the current study, we modeled the three-dimensional (3D) structure of the D2R based on a recently crystallized structure of the dopamine D3 receptor. These two receptors share a high amino acid sequence homology (>70%). The interaction of the modeled receptor with well-known atypical and typical anti-psychotic drugs and the inhibition mechanisms of drugs at the catalytic domain were studied via atomistic molecular dynamics simulations. Our results revealed that, class-I and class-II forms of atypical and typical D2R antagonists follow different pathways in the inhibition of the D2Rs.</p

Roadmap to Design Mechanically Robust Copolymer Hydrogels Naturally Cross-Linked by Hydrogen Bonds

Although several mechanically strong physical hydrogels bearing H-bond donor and acceptor groups have been reported over the past years, the effect of the complex interplay between competing interactions on the mechanical strength of H-bonded hydrogels remains a challenge. We present here the mechanical properties of six different copolymer hydrogels formed under identical conditions. Methacrylic acid (MAAc), acrylic acid (AAc), N,N-dimethylacrylamide (DMAA), 1-vinylimidazole (NVI), N-vinyl pyrrolidone (NVP), and acrylamide (AAm) monomers were copolymerized to form MAAc/DMAA, AAc/DMAA, AAc/NVI, MAAc/NVI, MAAc/NVP, and AAm/NVP hydrogels, respectively, at various molar ratios in the presence of 60 wt % water. The hydrophobicity of the monomers and the competing interactions between the copolymer chains and copolymer–water were quantitatively elucidated by the all-atom MD simulations in the explicit water, density functional theory calculations, and molecular descriptors by remaining faithful to the experimental compositions. Young’s modulus of the hydrogels could be varied between 10–1 and 101 MPa by changing the type and molar ratio of the comonomers. AAc/DMAA and AAm/NVP hydrogels exhibit the lowest moduli, 0.11 ± 0.05 and 0.20 ± 0.04 MPa, respectively, over all comonomer compositions, while for all other comonomer pairs, the resulting hydrogels assume a maximum modulus at a critical composition. MAAc and NVI are the most effective major and minor components, respectively, to generate copolymer hydrogels with a high modulus and strength. The crucial factors determining the mechanical performance of the copolymer hydrogels are the hydrophobicity of the major copolymer component, ionic H-bonds, formation of strong H-bonded nanoaggregates, and stronger and higher inter-chain H-bonding and hence electrostatic interactions

Proposing Novel MAO‑B Hit Inhibitors Using Multidimensional Molecular Modeling Approaches and Application of Binary QSAR Models for Prediction of Their Therapeutic Activity, Pharmacokinetic and Toxicity Properties

Monoamine oxidase (MAO) enzymes MAO-A and MAO-B play a critical role in the metabolism of monoamine neurotransmitters. Hence, MAO inhibitors are very important for the treatment of several neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). In this study, 256 750 molecules from Otava Green Chemical Collection were virtually screened for their binding activities as MAO-B inhibitors. Two hit molecules were identified after applying different filters such as high docking scores and selectivity to MAO-B, desired pharmacokinetic profile predictions with binary quantitative structure–activity relationship (QSAR) models. Therapeutic activity prediction as well as pharmacokinetic and toxicity profiles were investigated using MetaCore/MetaDrug platform which is based on a manually curated database of molecular interactions, molecular pathways, gene–disease associations, chemical metabolism, and toxicity information. Particular therapeutic activity and toxic effect predictions are based on the ChemTree ability to correlate structural descriptors to that property using recursive partitioning algorithm. Molecular dynamics (MD) simulations were also performed to make more detailed assessments beyond docking studies. All these calculations were made not only to determine if studied molecules possess the potential to be a MAO-B inhibitor but also to find out whether they carry MAO-B selectivity versus MAO-A. The evaluation of docking results and pharmacokinetic profile predictions together with the MD simulations enabled us to identify one hit molecule (ligand <b>1</b>, Otava ID: 3463218) which displayed higher selectivity toward MAO-B than a positive control selegiline which is a commercially used drug for PD therapeutic purposes

Discovering novel carbonic anhydrase type IX (CA IX) inhibitors from seven million compounds using virtual screening and <i>in vitro</i> analysis

<p>Carbonic anhydrase type IX (CA IX) enzyme is mostly over expressed in different cancer cell lines and tumor tissues. Potent CA IX inhibitors can be effective for adjusting the pH imbalance in tumor cells. In the present work, we represented the successful application of high throughput virtual screening (HTVS) of large dataset from ZINC database included of ∼7 million compounds to discover novel inhibitors of CA IX. HTVS and molecular docking were performed using consequence Glide/standard precision (SP), extra precision (XP) and induced fit docking (IFD) molecular docking protocols. For each compound, docking code calculates a set of low-energy poses and then exhaustively scans the binding pocket of the target with small compounds. Novel CA IX inhibitor candidates were suggested based on molecular modeling studies and a few of them were tested using <i>in vitro</i> analysis. These compounds were determined as good inhibitors against human CA IX target with K_i in the range of 0.85–1.58 μM. In order to predict the pharmaceutical properties of the selected compounds, ADME (absorption, distribution, metabolism and excretion) analysis was also carried out.</p

Mutated form (G52E) of inactive diphtheria toxin CRM197: molecular simulations clearly display effect of the mutation to NAD binding

<p>Mutated form (G52E) of diphtheria toxin (DT) CRM197 is an inactive and nontoxic enzyme. Here, we provided a molecular insight using comparative molecular dynamics (MD) simulations to clarify the influence of a single point mutation on overall protein and active-site loop. Post-processing MD analysis (i.e. stability, principal component analysis, hydrogen-bond occupancy, etc.) is carried out on both wild and mutated targets to investigate and to better understand the mechanistic differences of structural and dynamical properties on an atomic scale especially at nicotinamide adenine dinucleotide (NAD) binding site when a single mutation (G52E) happens at the DT. In addition, a docking simulation is performed for wild and mutated forms. The docking scoring analysis and docking poses results revealed that mutant form is not able to properly accommodate the NAD molecule.</p

Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques

We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor–receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model

<i>In silico</i> investigation of PARP-1 catalytic domains in <i>holo</i> and <i>apo</i> states for the design of high-affinity PARP-1 inhibitors

<div><p></p><p>The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened <i>in silico</i> at the central cavities of hERG1 potassium ion channel.</p></div

Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of <i>in silico</i> and <i>in vitro</i> studies

Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking – IFD, and quantum mechanics polarized ligand docking – QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63 μM against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.</p

Biological Insights of the Dopaminergic Stabilizer ACR16 at the Binding Pocket of Dopamine D2 Receptor

The dopamine D2 receptor (D2R) plays an important part in the human central nervous system and it is considered to be a focal target of antipsychotic agents. It is structurally modeled in active and inactive states, in which homodimerization reaction of the D2R monomers is also applied. The ASP2314 (also known as ACR16) ligand, a D2R stabilizer, is used in tests to evaluate how dimerization and conformational changes may alter the ligand binding space and to provide information on alterations in inhibitory mechanisms upon activation. The administration of the D2R agonist ligand ACR16 [³H]­(+)-4-propyl-3,4,4<i>a</i>,5,6,10<i>b</i>-hexahydro-2<i>H</i>-naphtho­[1,2-<i>b</i>]­[1,4]­oxazin-9-ol ((+)­PHNO) revealed <i>K</i>_i values of 32 nM for the D2^highR and 52 μM for the D2^lowR. The calculated binding affinities of ACR16 with post processing molecular dynamics (MD) simulations analyses using MM/PBSA for the monomeric and homodimeric forms of the D2^highR were −9.46 and −8.39 kcal/mol, respectively. The data suggests that the dimerization of the D2R leads negative cooperativity for ACR16 binding. The dimerization reaction of the D2^highR is energetically favorable by −22.95 kcal/mol. The dimerization reaction structurally and thermodynamically stabilizes the D2^highR conformation, which may be due to the intermolecular forces formed between the TM4 of each monomer, and the result strongly demonstrates dimerization essential for activation of the D2R

Metal-Catalyzed Cyclization Reactions of Carbonyl Ylides: Synthesis and DFT Study of Mechanisms

1,3-Dioxole derivatives were synthesized from copper(II)-catalyzed cyclization reactions of carbonyl ylides derived from 3-methylenebicyclo[2.2.1]heptan-2-one and dimethyl diazomalonate. The reaction mechanisms leading to all possible products have been extensively investigated by density functional theory. The generally accepted mechanism proposed by Doyle12 for the carbene transformation reactions were applied to this system for the first time to shed light on the reaction mechanism and to understand the catalytic activity of Cu(acac)2. Calculations have shown that the reaction mechanisms leading to different products greatly depend on the conformations of copper-stabilized carbonyl ylides, which are treated as reactants in our calculations. The conformational effects and donor−acceptor type stabilizations between the catalyst and the carbonyl ylide observed in the reactants and the transition state geometries seem to be the main reasons for the observed product selectivity. Our theoretical results are in good agreement with the experimental results, and the calculations successfully predict the experimental 75:25 product distribution