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

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

Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking

Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2^HighR and D2^LowR dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2^HighR and D2^LowR targets were −12.04 and −9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2^HighR and D2^LowR with binding affinities (<i>K</i>_i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [³H]­domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2^HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2^HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2^LowR. Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models

Analysis of the Glutamate Agonist LY404,039 Binding to Nonstatic Dopamine Receptor D2 Dimer Structures and Consensus Docking

Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2^HighR and D2^LowR dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2^HighR and D2^LowR targets were −12.04 and −9.11 kcal/mol, respectively. The experimental results suggest that LY404,039 binds to D2^HighR and D2^LowR with binding affinities (<i>K</i>_i) of 8.2 and 1640 nM, respectively. The high binding affinity of LY404,039 in terms of binding to [³H]­domperidone was inhibited by the presence of a guanine nucleotide, indicating an agonist action of the drug at D2^HighR. The interaction analysis demonstrated that while Asp114 was among the most critical amino acids for D2^HighR binding, residues Ser193 and Ser197 were significantly more important within the binding cavity of D2^LowR. Molecular modeling analyses are extended to ensemble docking as well as structure-based pharmacophore model (E-pharmacophore) development using the bioactive conformation of LY404,039 at the binding pocket as a template and screening of small-molecule databases with derived pharmacophore models

Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors

<p>New coumaryl-carboxamide derivatives with the thiourea moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and their inhibitory activity against the human carbonic anhydrase (hCA) isoforms hCA I, II, VII and IX were evaluated. While the hCA I, II and VII isoforms were not inhibited by the investigated compounds, the tumour-associated isoform hCA IX was inhibited in the high nanomolar range. 2-Oxo-<i>N</i>-((2-(pyrrolidin-1-yl)ethyl)carbamothioyl)-<i>2H</i>-chromene-3-carboxamide (<b>e11</b>) exhibited a selective inhibitory action against hCA IX with the <i>K</i>_i of 107.9 nM. In order to better understand the inhibitory profiles of studied molecules, multiscale molecular modeling approaches were used. Different molecular docking algorithms were used to investigate binding poses and predicted binding energies of studied compounds at the active sites of the CA I, II, VII and IX isoforms.</p