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

Structural Investigation of the Dopamine‑2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR States

The active (D2HighR) and inactive (D2LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2HighR active state. There is good agreement between the calculated and experimentally measured D2HighR selectivity. In the ligand-binding site, the key amino acids identified for D2HighR were Asp114(3.32) and Glu95(2.65), and for D2LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2HighR state and more flexible at the D2LowR state. However, the side chains of the ligand–receptor complex of D2HighR showed larger variations relative to the corresponding regions of D2LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding

Structural Investigation of the Dopamine‑2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR States

The active (D2^HighR) and inactive (D2^LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2^HighR active state. There is good agreement between the calculated and experimentally measured D2^HighR selectivity. In the ligand-binding site, the key amino acids identified for D2^HighR were Asp114(3.32) and Glu95(2.65), and for D2^LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2^HighR state and more flexible at the D2^LowR state. However, the side chains of the ligand–receptor complex of D2^HighR showed larger variations relative to the corresponding regions of D2^LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding

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

Structural Investigation of the Dopamine‑2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR States

The active (D2^HighR) and inactive (D2^LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2^HighR active state. There is good agreement between the calculated and experimentally measured D2^HighR selectivity. In the ligand-binding site, the key amino acids identified for D2^HighR were Asp114(3.32) and Glu95(2.65), and for D2^LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2^HighR state and more flexible at the D2^LowR state. However, the side chains of the ligand–receptor complex of D2^HighR showed larger variations relative to the corresponding regions of D2^LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding

Structural Investigation of the Dopamine‑2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR States

The active (D2^HighR) and inactive (D2^LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2^HighR active state. There is good agreement between the calculated and experimentally measured D2^HighR selectivity. In the ligand-binding site, the key amino acids identified for D2^HighR were Asp114(3.32) and Glu95(2.65), and for D2^LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2^HighR state and more flexible at the D2^LowR state. However, the side chains of the ligand–receptor complex of D2^HighR showed larger variations relative to the corresponding regions of D2^LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding

Structural Investigation of the Dopamine‑2 Receptor Agonist Bromocriptine Binding to Dimeric D2^HighR and D2^LowR States

The active (D2^HighR) and inactive (D2^LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor. Based on the MM/GBSA approach, the calculated binding enthalpies of bromocriptine demonstrated selectivity toward the D2^HighR active state. There is good agreement between the calculated and experimentally measured D2^HighR selectivity. In the ligand-binding site, the key amino acids identified for D2^HighR were Asp114(3.32) and Glu95(2.65), and for D2^LowR, it was Ser193(5.42). Moreover, analysis of replicate MD trajectories demonstrated that the bromocriptine structure was more rigid at the D2^HighR state and more flexible at the D2^LowR state. However, the side chains of the ligand–receptor complex of D2^HighR showed larger variations relative to the corresponding regions of D2^LowR. The present study is part of an ongoing research program to study D2R conformational changes during ligand activation and to evaluate the conformational state selectivity for ligand binding

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