Research

19 pages, 11554 KiB

Open AccessArticle

Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity

by Ítalo Antônio Fernandes, Déborah Braga Resende, Teodorico Castro Ramalho, Kamil Kuca and Elaine Fontes Ferreira da Cunha

Molecules 2020, 25(7), 1726; https://doi.org/10.3390/molecules25071726 - 09 Apr 2020

Cited by 8 | Viewed by 2405

Abstract

FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin−2-one derivatives, structurally [...] Read more.

FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin−2-one derivatives, structurally similar to Sunitinib. Molegro Virtual Docker (MVD) software was utilized in docking analyses. The predicted model of the training group, considering nineteen amino acid residues, performed in Chemoface, achieved an R² of 0.82, suggesting that the binding conformations of the ligands with FLT3 are reasonable, and the data can be used to predict the interaction energy of other FLT3 inhibitors with similar molecular patterns. The MolDock Score for energy for compound 1 showed more stable interaction energy (–233.25 kcal mol⁻¹) than the other inhibitors studied, while Sunitinib presented as one of the least stable (–160.94 kcal mol⁻¹). Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 can be highlighted as promising derivatives for synthesis and biological evaluation against FLT3. Furthermore, IAF79 can be considered to be a promising dual Aurora B/FLT3 inhibitor, and its molecular pattern can be exploited synthetically to search for new indolin−2-one derivatives that may become drugs used in the treatment of cancers, including AML. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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22 pages, 4854 KiB

Open AccessArticle

Multiclass Classifier for P-Glycoprotein Substrates, Inhibitors, and Non-Active Compounds

by Liadys Mora Lagares, Nikola Minovski and Marjana Novič

Molecules 2019, 24(10), 2006; https://doi.org/10.3390/molecules24102006 - 25 May 2019

Cited by 19 | Viewed by 4821

Abstract

P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by [...] Read more.

P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model’s performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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11 pages, 1292 KiB

Open AccessArticle

Lipophilicity as a Central Component of Drug-Like Properties of Chalchones and Flavonoid Derivatives

by Teodora Constantinescu, Claudiu Nicolae Lungu and Ildiko Lung

Molecules 2019, 24(8), 1505; https://doi.org/10.3390/molecules24081505 - 17 Apr 2019

Cited by 41 | Viewed by 3364

Abstract

Lipophilcity is an important physico-chemical parameter that influences membrane transport and binding ability to action. Migration distance following complete elution of compounds was used to calculate different lipophilicity-related parameters. The aim of this study is to show that lipophilicity is a central component [...] Read more.

Lipophilcity is an important physico-chemical parameter that influences membrane transport and binding ability to action. Migration distance following complete elution of compounds was used to calculate different lipophilicity-related parameters. The aim of this study is to show that lipophilicity is a central component of thiazole chalcones and flavonoid derivatives regarding their drug-like properties. Experimental and computational methods were used. This study considers 44 previously synthesized compounds (thiazole chalcones, flavanones, flavones, 3-hydroxyflavones, and their acetylated derivatives). The concerned compounds have shown antitumoral hallmarks and antibacterial activity in vitro. The experimental method used to determine compounds’ lipophilicity was the reverse-phase thin layer chromatography (RP-TLC). Lipophilicity related parameters—isocratic retention factor (R_M), relative lipophily (R_M⁰), slope (b), chromatographic hydrophobic index (φ₀), scores of principal components (PC1/R_M)—were determined based on reverse-phase chromatography results. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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14 pages, 4780 KiB

Open AccessArticle

MoleGear: A Java-Based Platform for Evolutionary De Novo Molecular Design

by Yunhan Chu and Xuezhong He

Molecules 2019, 24(7), 1444; https://doi.org/10.3390/molecules24071444 - 11 Apr 2019

Cited by 9 | Viewed by 4006

Abstract

A Java-based platform, MoleGear, is developed for de novo molecular design based on the chemistry development kit (CDK) and other Java packages. MoleGear uses evolutionary algorithm (EA) to explore chemical space, and a suite of fragment-based operators of growing, crossover, and mutation for [...] Read more.

A Java-based platform, MoleGear, is developed for de novo molecular design based on the chemistry development kit (CDK) and other Java packages. MoleGear uses evolutionary algorithm (EA) to explore chemical space, and a suite of fragment-based operators of growing, crossover, and mutation for assembling novel molecules that can be scored by prediction of binding free energy or a weighted-sum multi-objective fitness function. The EA can be conducted in parallel over multiple nodes to support large-scale molecular optimizations. Some complementary utilities such as fragment library design, chemical space analysis, and graphical user interface are also integrated into MoleGear. The candidate molecules as inhibitors for the human immunodeficiency virus 1 (HIV-1) protease were designed by MoleGear, which validates the potential capability for de novo molecular design. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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10 pages, 3199 KiB

Open AccessArticle

Cube-Related Corner Coalesced Nets

by Mircea V. Diudea

Molecules 2019, 24(7), 1221; https://doi.org/10.3390/molecules24071221 - 28 Mar 2019

Cited by 2 | Viewed by 2213

Abstract

Finite or periodic structures containing the cube motif can be synthesized and transformed into a variety of structures both at the theoretical and real, experimental level. The rhombellation topo-geometric operation may be used to transform the cube-shape into larger units and then build [...] Read more.

Finite or periodic structures containing the cube motif can be synthesized and transformed into a variety of structures both at the theoretical and real, experimental level. The rhombellation topo-geometric operation may be used to transform the cube-shape into larger units and then build light (spongy) structures with larger voids. Hyper-clusters are polyhedral structures which nodes are polyhedral structures (the same or different ones). The paper presents some hypothetical spongy structures related to the cubic primitive pcu-net, with defects induced by cutting-off some atoms and/or bonds so that only corners are shared between two cubes. A diamondoid hyper-structure containing cube-coalesced corners was proposed for an eventual synthesis. The discussed structures are described in topological terms, particularly by sequential vertex connectivity and ring environment. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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20 pages, 1459 KiB

Open AccessArticle

Aflatoxin B₁–Formamidopyrimidine DNA Adducts: Relationships between Structures, Free Energies, and Melting Temperatures

by Martin Klvana and Urban Bren

Molecules 2019, 24(1), 150; https://doi.org/10.3390/molecules24010150 - 02 Jan 2019

Cited by 25 | Viewed by 4136

Abstract

Thermal stabilities of DNA duplexes containing Gua (g), α- (a) or β-anomer of formamidopyrimidine-N7-9-hydroxy-aflatoxin B₁ (b) differ markedly (T_m:

a < g < b

), but the underlying molecular origin of this experimentally observed [...] Read more.

Thermal stabilities of DNA duplexes containing Gua (g), α- (a) or β-anomer of formamidopyrimidine-N7-9-hydroxy-aflatoxin B₁ (b) differ markedly (T_m:

a < g < b

), but the underlying molecular origin of this experimentally observed phenomenon is yet to be identified and determined. Here, by employing explicit-solvent molecular dynamics simulations coupled with free-energy calculations using a combined linear-interaction-energy/linear-response-approximation approach, we explain the quantitative differences in T

_{m}

in terms of three structural features (bulkiness, order, and compactness) and three energetical contributions (non-polar, electrostatic, and preorganized-electrostatic), and thus advance the current understanding of the relationships between structures, free energies, and thermal stabilities of DNA double helices. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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19 pages, 1897 KiB

Open AccessArticle

Inverse Molecular Docking as a Novel Approach to Study Anticarcinogenic and Anti-Neuroinflammatory Effects of Curcumin

by Veronika Furlan, Janez Konc and Urban Bren

Molecules 2018, 23(12), 3351; https://doi.org/10.3390/molecules23123351 - 18 Dec 2018

Cited by 63 | Viewed by 8877

Abstract

Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated [...] Read more.

Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPK). By modulating signal transduction pathways, curcumin induces apoptosis in malignant cells, thus inhibiting cancer development and progression. Due to the lack of mechanistic insight in the scientific literature, we developed a novel inverse molecular docking protocol based on the CANDOCK algorithm. For the first time, we performed inverse molecular docking of curcumin into a collection of 13,553 available human protein structures from the Protein Data Bank resulting in prioritized target proteins of curcumin. Our predictions were in agreement with the scientific literature and confirmed that curcumin binds to folate receptor β, DNA (cytosine-5)-methyltransferase 3A, metalloproteinase-2, mitogen-activated protein kinase 9, epidermal growth factor receptor and apoptosis-inducing factor 1. We also identified new potential protein targets of curcumin, namely deoxycytidine kinase, NAD-dependent protein deacetylase sirtuin-1 and -2, ecto-5′-nucleotidase, core histone macro-H2A.1, tyrosine-protein phosphatase non-receptor type 11, macrophage colony-stimulating factor 1 receptor, GTPase HRas, aflatoxin B1 aldehyde reductase member 3, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase, death-associated protein kinase 2 and tryptophan-tRNA ligase, that may all play a crucial role in its observed anticancer effects. Moreover, our inverse docking results showed that curcumin potentially binds also to the proteins cAMP-specific 3′,5′-cyclic phosphodiesterase 4D and 17-β-hydroxysteroid dehydrogenase type 10, which provides a new explanation for its efficiency in the treatment of Alzheimer’s disease. We firmly believe that our computational results will complement and direct future experimental studies on curcumin’s anticancer activity as well as on its therapeutic effects against Alzheimer’s disease. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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14 pages, 11751 KiB

Open AccessArticle

Cube-Rhombellane Related Structures: A Drug Perspective

by Mircea Vasile Diudea, Claudiu Nicolae Lungu and Csaba Levente Nagy

Molecules 2018, 23(10), 2533; https://doi.org/10.3390/molecules23102533 - 04 Oct 2018

Cited by 19 | Viewed by 3354

Abstract

Rhombellanes represent a new class of structures, of which homeomorphs may be synthesized as real molecules. Cube-rhombellane is a double-shell structure, with vertices of degree 3 and 6, respectively. Several hypothetical structures/molecules were proposed and computed using molecular graph theory and coordination chemistry [...] Read more.

Rhombellanes represent a new class of structures, of which homeomorphs may be synthesized as real molecules. Cube-rhombellane is a double-shell structure, with vertices of degree 3 and 6, respectively. Several hypothetical structures/molecules were proposed and computed using molecular graph theory and coordination chemistry principles. Some geometries were optimized at the B3LYP/6-31G (d, p) level of theory, followed by harmonic vibrational frequency analysis at the same level of theory, single point data were collected in view of molecular stability evaluation. Some of the bioactive functionalized structures were also proposed and explored by molecular mechanics (MM)-based conformational analysis, to check their internal mobility. Drug-like properties of the proposed molecular structures were compared with some existing nano-molecules (fullerenes, nanotubes). ADME and other physico-chemical characteristics were computed using commercial software. Substructures of the proposed molecules, useful in a future synthesis, were provided by retro combinatorial synthesis (RECAP). Computational results obtained are promising regarding ADME properties, drug-likeness and nano-properties. Full article

(This article belongs to the Special Issue Receptor-Dependent QSAR Methods)

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