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Article ; Online: Structural Modeling of TRPA1 Ion Channel-Determination of the Binding Site for Antagonists.

Gawalska, Alicja / Kołaczkowski, Marcin / Bucki, Adam

2022 Volume 27, Issue 10

Abstract: TRPA1 is a transmembrane cation channel, one of the most promising targets in the context of respiratory diseases. Its general structure has already been experimentally resolved, but the binding site of TRPA1 antagonists such as HC-030031, a model ... ...

Abstract	TRPA1 is a transmembrane cation channel, one of the most promising targets in the context of respiratory diseases. Its general structure has already been experimentally resolved, but the binding site of TRPA1 antagonists such as HC-030031, a model methylxanthine derivative, remains unknown. The present study aimed to determine the potential binding site of xanthine antagonists and to describe their binding mode, using a molecular modeling approach. This study represents the first attempt to bring together site-directed mutagenesis reports and the latest cryo-EM structure of an antagonist bound to TRPA1. Our research suggests that the core moiety of HC-030031 binds to a pocket formed by the TRP-like domain and the pre-S1, S4, S5 helices of one subunit. The structure, determined by cryo-EM, shows interactions of a core hypoxanthine moiety in the same area of the binding site, sharing the interaction of xanthine/hypoxanthine with Trp-711. Moreover, the predicted binding mode of HC-030031 assumes interaction with Asn-855, a residue demonstrated to be important for HC-030031 recognition in site-directed mutagenesis studies. Our model proved to be advantageous in a retrospective virtual screening benchmark; therefore, it will be useful in research on new TRPA1 antagonists among xanthine derivatives and their bioisosteres.
MeSH term(s)	Binding Sites ; Calcium Channels/metabolism ; Hypoxanthines ; Retrospective Studies ; TRPA1 Cation Channel/genetics ; TRPA1 Cation Channel/metabolism ; Xanthines
Chemical Substances	Calcium Channels ; Hypoxanthines ; TRPA1 Cation Channel ; Xanthines
Language	English
Publishing date	2022-05-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27103077
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Article ; Online: Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance.

Piska, Kamil / Koczurkiewicz-Adamczyk, Paulina / Jamrozik, Marek / Bucki, Adam / Kołaczkowski, Marcin / Pękala, Elżbieta

Xenobiotica; the fate of foreign compounds in biological systems

2023 Volume 53, Issue 6-7, Page(s) 507–514

Abstract: 1. ABCB1 (P-glycoprotein, MDR1) is one of the most important transporter involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and ... ...

Abstract	1. ABCB1 (P-glycoprotein, MDR1) is one of the most important transporter involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Several intracellular enzymes metabolise anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolite efflux by ABCB1 transporter is not well characterised, while it may be the mechanism responsible for the metabolites' lack of activity.2. In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modelling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux.3. Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 significantly affected the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicinol accumulation were influenced by the activity of ABCB1 modulator - valspodar.4. Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. Therefore crosstalk between the process of anthracyclines metabolism and metabolite efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.
MeSH term(s)	Humans ; Adenosine Triphosphatases/metabolism ; Anthracyclines/pharmacology ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Cell Line, Tumor ; Daunorubicin/pharmacology ; Doxorubicin/pharmacology ; Neoplasms
Chemical Substances	ABCB1 protein, human ; Adenosine Triphosphatases (EC 3.6.1.-) ; Anthracyclines ; ATP Binding Cassette Transporter, Subfamily B ; Daunorubicin (ZS7284E0ZP) ; daunorubicinol (YDU8YIP30L) ; Doxorubicin (80168379AG)
Language	English
Publishing date	2023-11-03
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	120287-x
ISSN	1366-5928 ; 0049-8254
ISSN (online)	1366-5928
ISSN	0049-8254
DOI	10.1080/00498254.2023.2264391
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Article ; Online: Novel 1-(1-Arylimiazolin-2-Yl)-3-Arylalkilurea Derivatives with Modulatory Activity on Opioid MOP Receptors.

Straszak, Dominik / Woźniak, Sylwia / Siwek, Agata / Głuch-Lutwin, Monika / Kołaczkowski, Marcin / Pietrzak, Aldona / Drop, Bartłomiej / Matosiuk, Dariusz

Molecules (Basel, Switzerland)

2024 Volume 29, Issue 3

Abstract: μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties ... ...

Abstract	μ-opioid receptor ligands such as morphine and fentanyl are the most known and potent painkillers. However, the severe side effects seen with their use significantly limit their widespread use. The continuous broadening of knowledge about the properties of the interactions of the MOP receptor (human mu opioid receptor, OP3) with ligands and specific intracellular signaling pathways allows for the designation of new directions of research with respect to compounds with analgesic effects in a mechanism different from classical ligands. Allosteric modulation is an extremely promising line of research. Compounds with modulator properties may provide a safer alternative to the currently used opioids. The aim of our research was to obtain a series of urea derivatives of 1-aryl-2-aminoimidazoline and to determine their activity, mechanism of biological action and selectivity toward the MOP receptor. The obtained compounds were subjected to functional tests (cAMP accumulation and β-arrestin recruitment) in vitro. One of the obtained compounds, when administered alone, did not show any biological activity, while when co-administered with DAMGO, it inhibited β-arrestin recruitment. These results indicate that this compound is a negative allosteric modulator (NAM) of the human MOP receptor.
MeSH term(s)	Humans ; Receptors, Opioid/metabolism ; Receptors, Opioid, mu/metabolism ; Analgesics, Opioid/adverse effects ; Analgesics/pharmacology ; beta-Arrestins/metabolism
Chemical Substances	Receptors, Opioid ; Receptors, Opioid, mu ; Analgesics, Opioid ; Analgesics ; beta-Arrestins
Language	English
Publishing date	2024-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules29030571
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Article ; Online: Application of automated machine learning in the identification of multi-target-directed ligands blocking PDE4B, PDE8A, and TRPA1 with potential use in the treatment of asthma and COPD.

Gawalska, Alicja / Czub, Natalia / Sapa, Michał / Kołaczkowski, Marcin / Bucki, Adam / Mendyk, Aleksander

Molecular informatics

2023 Volume 42, Issue 7, Page(s) e2200214

Abstract: Asthma and COPD are characterized by complex pathophysiology associated with chronic inflammation, bronchoconstriction, and bronchial hyperresponsiveness resulting in airway remodeling. A possible comprehensive solution that could fully counteract the ... ...

Abstract	Asthma and COPD are characterized by complex pathophysiology associated with chronic inflammation, bronchoconstriction, and bronchial hyperresponsiveness resulting in airway remodeling. A possible comprehensive solution that could fully counteract the pathological processes of both diseases are rationally designed multi-target-directed ligands (MTDLs), combining PDE4B and PDE8A inhibition with TRPA1 blockade. The aim of the study was to develop AutoML models to search for novel MTDL chemotypes blocking PDE4B, PDE8A, and TRPA1. Regression models were developed for each of the biological targets using "mljar-supervised". On their basis, virtual screenings of commercially available compounds derived from the ZINC15 database were performed. A common group of compounds placed within the top results was selected as potential novel chemotypes of multifunctional ligands. This study represents the first attempt to discover the potential MTDLs inhibiting three biological targets. The obtained results prove the usefulness of AutoML methodology in the identification of hits from the big compound databases.
MeSH term(s)	Humans ; Ligands ; Asthma/drug therapy ; Pulmonary Disease, Chronic Obstructive/drug therapy ; TRPA1 Cation Channel ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; 3',5'-Cyclic-AMP Phosphodiesterases
Chemical Substances	Ligands ; TRPA1 protein, human ; TRPA1 Cation Channel ; PDE4B protein, human (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17) ; PDE8A protein, human (EC 3.1.4.17) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17)
Language	English
Publishing date	2023-06-16
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537668-8
ISSN	1868-1751 ; 1868-1743
ISSN (online)	1868-1751
ISSN	1868-1743
DOI	10.1002/minf.202200214
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Article: Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice.

Żmudzka, Elżbieta / Lustyk, Klaudia / Głuch-Lutwin, Monika / Wolak, Małgorzata / Jaśkowska, Jolanta / Kołaczkowski, Marcin / Sapa, Jacek / Pytka, Karolina

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 2

Abstract: Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness ...

Abstract	Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT
Language	English
Publishing date	2023-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16020175
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Article ; Online: In Silico and In Vitro Assessment of Carbonyl Reductase 1 Inhibition Using ASP9521-A Potent Aldo-Keto Reductase 1C3 Inhibitor with the Potential to Support Anticancer Therapy Using Anthracycline Antibiotics.

Jamrozik, Marek / Piska, Kamil / Bucki, Adam / Koczurkiewicz-Adamczyk, Paulina / Sapa, Michał / Władyka, Benedykt / Pękala, Elżbieta / Kołaczkowski, Marcin

Molecules (Basel, Switzerland)

2023 Volume 28, Issue 9

Abstract: Anthracycline antibiotics (ANT) are among the most widely used anticancer drugs. Unfortunately, their use is limited due to the development of drug resistance and cardiotoxicity. ANT metabolism, performed mainly by two enzymes-aldo-keto reductase 1C3 ( ... ...

Abstract	Anthracycline antibiotics (ANT) are among the most widely used anticancer drugs. Unfortunately, their use is limited due to the development of drug resistance and cardiotoxicity. ANT metabolism, performed mainly by two enzymes-aldo-keto reductase 1C3 (AKR1C3) and carbonyl reductase 1 (CBR1)-is one of the proposed mechanisms generated by the described effects. In this study, we evaluated the CBR1 inhibitory properties of ASP9521, a compound already known as potent AKR1C3 inhibitor. First, we assessed the possibility of ASP9521 binding to the CBR1 catalytic site using molecular docking and molecular dynamics. The research revealed a potential binding mode of ASP9521. Moderate inhibitory activity against CBR1 was observed in studies with recombinant enzymes. Finally, we examined whether ASP9521 can improve the cytotoxic activity of daunorubicin against human lung carcinoma cell line A549 and assessed the cardioprotective properties of ASP9521 in a rat cardiomyocytes model (H9c2) against doxorubicin- and daunorubicin-induced toxicity. The addition of ASP9521 ameliorated the cytotoxic activity of daunorubicin and protected rat cardiomyocytes from the cytotoxic effect of both applied drugs. Considering the favorable bioavailability and safety profile of ASP9521, the obtained results encourage further research. Inhibition of both AKR1C3 and CBR1 may be a promising method of overcoming ANT resistance and cardiotoxicity.
MeSH term(s)	Humans ; Rats ; Animals ; Carbonyl Reductase (NADPH) ; Molecular Docking Simulation ; Cardiotoxicity ; Anthracyclines/pharmacology ; Anthracyclines/metabolism ; Antibiotics, Antineoplastic/pharmacology ; Daunorubicin/pharmacology ; Antineoplastic Agents/pharmacology ; Anti-Bacterial Agents
Chemical Substances	Carbonyl Reductase (NADPH) (EC 1.1.1.184) ; 1-(1-((5-methoxy-1H-indol-2-yl)carbonyl)piperidin-4-yl)-2-methylpropan-2-ol ; Anthracyclines ; Antibiotics, Antineoplastic ; Daunorubicin (ZS7284E0ZP) ; Antineoplastic Agents ; Anti-Bacterial Agents
Language	English
Publishing date	2023-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28093767
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Article ; Online: 2-(4-Fluorophenyl)-1

Marcinkowska, Monika / Fajkis-Zajączkowska, Nikola / Szafrańska, Katarzyna / Jończyk, Jakub / Siwek, Agata / Mordyl, Barbara / Karcz, Tadeusz / Latacz, Gniewomir / Kolaczkowski, Marcin

ACS chemical neuroscience

2023 Volume 14, Issue 6, Page(s) 1166–1180

Abstract: Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided ... ...

Abstract	Modulation of α1β2γ2GABA-A receptor subpopulation expressed in the basal ganglia region is a conceptually novel mode of pharmacological strategy that offers prospects to tackle a variety of neurological dysfunction. Although clinical findings provided compelling evidence for the validity of this strategy, the current chemical space of molecules able to modulate the α1/γ2 interface of the GABA-A receptor is limited to imidazo[1,2-
MeSH term(s)	Receptors, GABA-A/metabolism ; Imidazoles/pharmacology ; Ligands ; Allosteric Regulation
Chemical Substances	Receptors, GABA-A ; Imidazoles ; Ligands
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00800
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Article: Potential Anti-Amnesic Activity of a Novel Multimodal Derivative of Salicylamide, JJGW08, in Mice.

Żmudzka, Elżbieta / Lustyk, Klaudia / Sałaciak, Kinga / Siwek, Agata / Jaśkowska, Jolanta / Kołaczkowski, Marcin / Sapa, Jacek / Pytka, Karolina

Pharmaceuticals (Basel, Switzerland)

2023 Volume 16, Issue 3

Abstract: Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions ... ...

Abstract	Memory impairments constitute a significant problem worldwide, and the COVID-19 pandemic dramatically increased the prevalence of cognitive deficits. Patients with cognitive deficits, specifically memory disturbances, have underlying comorbid conditions such as schizophrenia, anxiety, or depression. Moreover, the available treatment options have unsatisfactory effectiveness. Therefore, there is a need to search for novel procognitive and anti-amnesic drugs with additional pharmacological activity. One of the important therapeutic targets involved in the modulation of learning and memory processes are serotonin receptors, including 5-HT
Language	English
Publishing date	2023-03-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph16030399
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Article ; Online: Neuroprotective Activity of Enantiomers of Salsolinol and

Kurnik-Łucka, Magdalena / Latacz, Gniewomir / Bucki, Adam / Rivera-Meza, Mario / Khan, Nadia / Konwar, Jahnobi / Skowron, Kamil / Kołaczkowski, Marcin / Gil, Krzysztof

ACS omega

2023 Volume 8, Issue 41, Page(s) 38566–38576

Abstract: Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that ...

Abstract	Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that
Language	English
Publishing date	2023-10-05
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c05527
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Article ; Online: Metabolic and cardiovascular benefits and risks of 4-hydroxy guanabenz hydrochloride: α

Kotańska, Magdalena / Marcinkowska, Monika / Kuder, Kamil J / Walczak, Maria / Bednarski, Marek / Siwek, Agata / Kołaczkowski, Marcin

Pharmacological reports : PR

2023 Volume 75, Issue 5, Page(s) 1211–1229

Abstract: Background: α: Methods: We performed in silico analyses, involving molecular docking to targets of specific interest as well as other potential biological targets. In vitro investigations were conducted to assess the selectivity profile of 4-OH- ... ...

Abstract	Background: α Methods: We performed in silico analyses, involving molecular docking to targets of specific interest as well as other potential biological targets. In vitro investigations were conducted to assess the selectivity profile of 4-OH-Guanabenz binding to α-adrenoceptors, along with intrinsic activity studies involving α Results: 4-OH-guanabenz is a partial agonist of α Conclusions: The precise sequence of molecular events within the organism, linking the impact of 4-OH-Guanabenz on α
Language	English
Publishing date	2023-08-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2186248-5
ISSN	2299-5684 ; 1734-1140
ISSN (online)	2299-5684
ISSN	1734-1140
DOI	10.1007/s43440-023-00518-9
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