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18 pages, 4452 KiB

Open AccessArticle

Role of Non-Covalent Interactions in Carbonic Anhydrase I—Topiramate Complex Based on QM/MM Approach

by Kamil Wojtkowiak and Aneta Jezierska

Pharmaceuticals 2023, 16(4), 479; https://doi.org/10.3390/ph16040479 - 23 Mar 2023

Viewed by 1389

Carbonic anhydrase (CA) I with a Topiramate (TPM) complex was investigated on the basis of a Quantum Mechanics/Molecular Mechanics (QM/MM) approach. The QM part was treated using Density Functional Theory (DFT) while the MM was simulated using Amberff14SB and GAFF force fields. In [...] Read more.

Carbonic anhydrase (CA) I with a Topiramate (TPM) complex was investigated on the basis of a Quantum Mechanics/Molecular Mechanics (QM/MM) approach. The QM part was treated using Density Functional Theory (DFT) while the MM was simulated using Amberff14SB and GAFF force fields. In addition, the TIP3P model was applied to reproduce the polar environment influence on the studied complex. Next, three snapshots (after 5 ps, 10 ps, and 15 ps of the simulation time) were taken from the obtained trajectory to provide an insight into the non-covalent interactions present between the ligand and binding pocket of the protein. Our special attention was devoted to the binding site rearrangement, which is known in the literature concerning the complex. This part of the computations was performed using

ω

B97X functional with Grimme D3 dispersion corrections as well as a Becke–Johnson damping function (D3-BJ). Two basis sets were applied: def2-SVP (for larger models) and def2-TZVPD (for smaller models), respectively. In order to detect and describe non-covalent interactions between amino acids of the binding pocket and the ligand, Independent Gradient Model based on Hirshfeld partitioning (IGMH), Interaction Region Indicator (IRI), Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbitals (NBO) methods were employed. Finally, Symmetry-Adapted Perturbation Theory (SAPT) was applied for energy decomposition between the ligand and protein. It was found that during the simulation time, the ligand position in the binding site was preserved. Nonetheless, amino acids interacting with TPM were exchanging during the simulation, thus showing the binding site reorganization. The energy partitioning revealed that dispersion and electrostatics are decisive factors that are responsible for the complex stability. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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11 pages, 1962 KiB

Open AccessArticle

Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions

by David Ngo, Angel J. Magaña, Tung Tran, Jan Sklenicka, Kimberly Phan, Brian Eykholt, Verónica Jimenez, María S. Ramirez and Marcelo E. Tolmasky

Pharmaceuticals 2023, 16(2), 236; https://doi.org/10.3390/ph16020236 - 03 Feb 2023

Cited by 2 | Viewed by 1937

Abstract

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule [...] Read more.

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-N-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag⁺, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the bla_TEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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18 pages, 3622 KiB

Open AccessArticle

Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

by Monika Kupiec, Agnieszka Tomaszewska, Wioletta Jakubczak, Maja Haczyk-Więcek and Katarzyna Pawlak

Pharmaceuticals 2022, 15(10), 1285; https://doi.org/10.3390/ph15101285 - 19 Oct 2022

Cited by 3 | Viewed by 1912

Abstract

Two types of lung cells (epithelial cancer lung cells, A-549 and lung fibroblasts MRC-5) were exposed to the clinically established gold drug auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC₅₀). Collected cells were subjected to speciation analysis using [...] Read more.

Two types of lung cells (epithelial cancer lung cells, A-549 and lung fibroblasts MRC-5) were exposed to the clinically established gold drug auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC₅₀). Collected cells were subjected to speciation analysis using inductively coupled plasma mass spectrometry (ICP-MS). Auranofin showed better affinity toward proteins than DNA, RNA, and hydrophilic small molecular weight compounds. It can bind to proteins that vary in size (~20 kDa, ~75 kDa, and ≥200 kDa) and pI. However, the possibility of dimerization and protein–protein complex formation should also be taken into account. µRPLC/CZE-ESI-MS/MS studies on trypsinized proteins allowed the indication of 76 peptides for which signal intensity was influenced by auranofin presence in cells. Based on it, identity was proposed for 20 proteins. Except for thioredoxin reductase (TrxR), which is directly targeted by gold complex, the proteins were found to be transformed. Five indicated proteins: myosin, plectin, talin, two annexins, and kinase M3K5, are responsible for cell–cell, cell–protein interactions, and cell motility. A wound healing test confirmed their regulation by auranofin as cell migration decreased by 40% while the cell cycle was not interrupted. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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32 pages, 5052 KiB

Open AccessArticle

A Study on Repositioning Nalidixic Acid via Lanthanide Complexation: Synthesis, Characterization, Cytotoxicity and DNA/Protein Binding Studies

by Ana-Madalina Maciuca, Alexandra-Cristina Munteanu, Mirela Mihaila, Mihaela Badea, Rodica Olar, George Mihai Nitulescu, Cristian V. A. Munteanu and Valentina Uivarosi

Pharmaceuticals 2022, 15(8), 1010; https://doi.org/10.3390/ph15081010 - 17 Aug 2022

Cited by 4 | Viewed by 1981

Abstract

“Drug repositioning” is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La [...] Read more.

“Drug repositioning” is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺); the experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms, findings that are supported by DFT calculations. The cytotoxic activity of the complexes has been studied using the tumoral cell lines, MDA-MB-231 and LoVo, and a normal cell line, HUVEC. The most active compounds of the series display selective activity against LoVo. Their affinity for DNA and the manner of binding have been tested using UV–Vis spectroscopy and competitive binding studies; our results indicate that major and minor groove binding play a significant role in these interactions. The affinity towards serum proteins has also been evaluated, the complexes displaying higher affinity towards albumin than apotransferrin. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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19 pages, 2298 KiB

Open AccessArticle

Design and Anticancer Properties of New Water-Soluble Ruthenium–Cyclopentadienyl Complexes

by Tânia S. Morais, Fernanda Marques, Paulo J. Amorim Madeira, Maria Paula Robalo and Maria Helena Garcia

Pharmaceuticals 2022, 15(7), 862; https://doi.org/10.3390/ph15070862 - 14 Jul 2022

Cited by 7 | Viewed by 2100

Abstract

Ruthenium complexes are emerging as one of the most promising classes of complexes for cancer therapy. However, their limited aqueous solubility may be the major limitation to their potential clinical application. In view and to contribute to the progress of this field, eight [...] Read more.

Ruthenium complexes are emerging as one of the most promising classes of complexes for cancer therapy. However, their limited aqueous solubility may be the major limitation to their potential clinical application. In view and to contribute to the progress of this field, eight new water-soluble Ru(II) organometallic complexes of general formula [RuCp(mTPPMS)_n(L)] [CF₃SO₃], where mTPPMS = diphenylphosphane-benzene-3-sulfonate, for n = 2, L is an imidazole-based ligand (imidazole, 1-benzylimidazole, 1-butylimidazole, (1-(3-aminopropyl)imidazole), and (1-(4-methoxyphenyl)imidazole)), and for n = 1, L is a bidentate heteroaromatic ligand (2-benzoylpyridine, (di(2-pyridyl)ketone), and (1,2-(2-pyridyl)benzo-[b]thiophene)) were synthesized and characterized. The new complexes were fully characterized by NMR, FT-IR, UV–vis., ESI-HRMS, and cyclic voltammetry, which confirmed all the proposed molecular structures. The antiproliferative potential of the new Ru(II) complexes was evaluated on MDAMB231 breast adenocarcinoma, A2780 ovarian carcinoma, and HT29 colorectal adenocarcinoma cell lines, showing micromolar (MDAMB231 and HT29) and submicromolar (A2780) IC₅₀ values. The interaction of complex 6 with human serum albumin (HSA) and fatty-acid-free human serum albumin (HSA^faf) was evaluated by fluorescence spectroscopy techniques, and the results revealed that the ruthenium complex strongly quenches the intrinsic fluorescence of albumin in both cases. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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15 pages, 2430 KiB

Open AccessArticle

The Synthesis, Characterization, Molecular Docking and In Vitro Antitumor Activity of Benzothiazole Aniline (BTA) Conjugated Metal-Salen Complexes as Non-Platinum Chemotherapeutic Agents

by Md. Kamrul Islam, Seongmin Ha, Ah-Rum Baek, Byeong-Woo Yang, Yeoun-Hee Kim, Hyun-Jin Park, Minsup Kim, Sung-Wook Nam, Gang-Ho Lee and Yongmin Chang

Pharmaceuticals 2022, 15(6), 751; https://doi.org/10.3390/ph15060751 - 15 Jun 2022

Cited by 5 | Viewed by 2656

Abstract

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals [...] Read more.

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L, MnL, FeL, CoL, and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC₅₀ than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL, CoL, and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL, remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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Review

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19 pages, 3281 KiB

Open AccessReview

Tris(aminomethyl)phosphines and Their Copper(I) (Pseudo)halide Complexes with Aromatic Diimines—A Critical Retrospection

by Radosław Starosta

Pharmaceuticals 2023, 16(5), 766; https://doi.org/10.3390/ph16050766 - 19 May 2023

Cited by 3 | Viewed by 1669

Abstract

Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics, combined with the specific properties of coordinated organic molecules, result in many different mechanisms of biological action, making each of the [...] Read more.

Metal complexes feature a wide range of available geometries, diversified lability, controllable hydrolytic stability, and easily available rich redox activity. These characteristics, combined with the specific properties of coordinated organic molecules, result in many different mechanisms of biological action, making each of the myriads of the classes of metal coordination compounds unique. This focused review presents combined and systematized results of the studies of a group of copper(I) (pseudo)halide complexes with aromatic diimines and tris(aminomethyl)phosphines of a general formula [CuX(NN)PR₃], where X = I⁻ or NCS⁻, NN = 2,2′-bipyridyl, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline or 2,2′-biquinoline, and PR₃ = air-stable tris(aminomethyl)phosphines. The structural and electronic properties of the phosphine ligands and luminescent complexes are discussed. The complexes with 2,9-dimethyl-1,10-phenanthroline, apart from being air- and water-stable, exhibit a very high in vitro antimicrobial activity against the Staphylococcus aureus and Candida albicans. Moreover, some of these complexes also show a strong in vitro antitumor activity against human ovarian carcinoma cell lines: MDAH 2774 and SCOV 3, CT26 (mouse colon carcinoma), and A549 (human lung adenocarcinoma) cell lines. The tested complexes are moderately able to induce DNA lesions through free radical processes, however the trends do not reflect observed differences in biological activity. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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20 pages, 2500 KiB

Open AccessReview

What Is the Correlation between Preeclampsia and Cancer? The Important Role of Tachykinins and Transition Metal Ions

by Klaudia Szczerba and Kamila Stokowa-Soltys

Pharmaceuticals 2023, 16(3), 366; https://doi.org/10.3390/ph16030366 - 28 Feb 2023

Viewed by 2606

Abstract

Metal ions are irreplaceable in many biological processes. They are components of numerous metalloproteins and serve as cofactors or structural elements for enzymes. Interestingly, iron, copper and zinc play important roles in accelerating or preventing neoplastic cell transformation. Noteworthily, a lot of proliferative [...] Read more.

Metal ions are irreplaceable in many biological processes. They are components of numerous metalloproteins and serve as cofactors or structural elements for enzymes. Interestingly, iron, copper and zinc play important roles in accelerating or preventing neoplastic cell transformation. Noteworthily, a lot of proliferative and invasive mechanisms are exploited by both malignant tumors and pregnancy. Cancer cells, as well as developing placenta cells, create a microenvironment supportive of immunologic privilege and angiogenesis. Therefore, pregnancy and cancer progression share many similarities. Moreover, during preeclampsia and cancer, significant changes in relevant trace element concentrations, tachykinin levels, expressions of neurokinin receptors, oxidative stress and angiogenic imbalance are observed. This sheds a new light on the role of metal ions and tachykinins in cancer progression and pregnancy, especially in preeclamptic women. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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