Publications by authors named "Thales Kronenberger"

38 Publications

SARS-COV-2 M conformational changes induced by covalently bound ligands.

J Biomol Struct Dyn 2021 Sep 13:1-11. Epub 2021 Sep 13.

Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany.

SARS-CoV-2's main protease (M) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, M is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different M-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 μs per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the M dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 M.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1970626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442757PMC
September 2021

(E)-7-Ethylidene-lithocholic Acid (7-ELCA) Is a Potent Dual Farnesoid X Receptor (FXR) Antagonist and GPBAR1 Agonist Inhibiting FXR-Induced Gene Expression in Hepatocytes and Stimulating Glucagon-like Peptide-1 Secretion From Enteroendocrine Cells.

Front Pharmacol 2021 13;12:713149. Epub 2021 Aug 13.

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia.

Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC = 15 μM/EC = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
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http://dx.doi.org/10.3389/fphar.2021.713149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414367PMC
August 2021

Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27.

Eur J Med Chem 2021 Aug 14;225:113777. Epub 2021 Aug 14.

Laboratory of Molecular Pharmacology, GIGA-Molecular Biology of Diseases, University of Liège, Liège, Belgium; Laboratory of Medicinal Chemistry, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.

GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called "Super-Conserved Receptors Expressed in the Brain" (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC 6.34, E 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC 6.85, E 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC 6.04, E 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC 5.99, E 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
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http://dx.doi.org/10.1016/j.ejmech.2021.113777DOI Listing
August 2021

Conserved Salt Bridges Facilitate Assembly of the Helical Core Export Apparatus of a Salmonella enterica Type III Secretion System.

J Mol Biol 2021 Jul 22;433(19):167175. Epub 2021 Jul 22.

Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Tübingen, Germany; Excellence Cluster "Controlling Microbes to Fight Infections" (CMFI), Tübingen, Germany; Partner-site Tübingen, German Center for Infection Research (DZIF), Tübingen, Germany. Electronic address:

Virulence-associated type III secretion systems (T3SS) are utilized by Gram negative bacterial pathogens for injection of effector proteins into eukaryotic host cells. The transmembrane export apparatus at the core of T3SS is composed of a unique helical complex of the hydrophobic proteins SctR, SctS, SctT, and SctU. These components comprise a number of highly conserved charged residues within their hydrophobic domains. The structure of the closed state of the core complex SctRST revealed that several of these residues form inter- and intramolecular salt bridges, some of which have to be broken for pore opening. Mutagenesis of individual residues was shown to compromise assembly or secretion of both, the virulence-associated and the related flagellar T3SS. However, the exact role of these conserved charged residues in the assembly and function of T3SS remains elusive. Here we performed an in-depth mutagenesis analysis of these residues in the T3SS of Salmonella Typhimurium, coupled to blue native PAGE, in vivo photocrosslinking and luciferase-based secretion assays. Our data show that these conserved salt bridges are not critical for assembly of the respective protein but rather facilitate the incorporation of the following subunit into the assembling complex. Our data also indicate that these conserved charged residues are critical for type III-dependent secretion and reveal a functional link between SctS and SctT and the cytoplasmic domain of SctU in gating the T3SS injectisome. Overall, our analysis provides an unprecedented insight into the delicate requirements for the assembly and function of the machinery at the core of T3SS.
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http://dx.doi.org/10.1016/j.jmb.2021.167175DOI Listing
July 2021

Targeting SUMOylation in as a Potential Target for Malaria Therapy.

Front Cell Infect Microbiol 2021 10;11:685866. Epub 2021 Jun 10.

Department of Parasitology, Institute of Biomedical Sciences at the University of São Paulo, São Paulo, Brazil.

Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the genus are responsible for causing malaria in humans. species have a complex life cycle that requires post-translational modifications (PTMs) to control cellular activities temporally and spatially and regulate the levels of critical proteins and cellular mechanisms for maintaining an efficient infection and immune evasion. SUMOylation is a PTM formed by the covalent linkage of a small ubiquitin-like modifier protein to the lysine residues on the protein substrate. This PTM is reversible and is triggered by the sequential action of three enzymes: E1-activating, E2-conjugating, and E3 ligase. On the other end, ubiquitin-like-protein-specific proteases in yeast and sentrin-specific proteases in mammals are responsible for processing SUMO peptides and for deconjugating SUMOylated moieties. Further studies are necessary to comprehend the molecular mechanisms and cellular functions of SUMO in . The emergence of drug-resistant malaria parasites prompts the discovery of new targets and antimalarial drugs with novel mechanisms of action. In this scenario, the conserved biological processes regulated by SUMOylation in the malaria parasites such as gene expression regulation, oxidative stress response, ubiquitylation, and proteasome pathways, suggest SUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the SUMO during the coordinated multi-step life cycle of and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.
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http://dx.doi.org/10.3389/fcimb.2021.685866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224225PMC
July 2021

Quantitative structure-activity relationship and machine learning studies of 2-thiazolylhydrazone derivatives with anti- activity.

J Biomol Struct Dyn 2021 Jun 14:1-12. Epub 2021 Jun 14.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

is a fungus responsible for infections in humans with a significant number of cases in immunosuppressed patients, mainly in underdeveloped countries. In this context, the thiazolylhydrazones are a promising class of compounds with activity against . The understanding of the structure-activity relationship of these derivatives could lead to the design of robust compounds that could be promising drug candidates for fungal infections. Specifically, modern techniques such as 4D-QSAR and machine learning methods were employed in this work to generate two QSAR models (one 2D and one 4D) with high predictive power (r for the test set equals to 0.934 and 0.831, respectively), and one random forest classification model was reported with Matthews correlation coefficient equals to 1 and 0.62 for internal and external validations, respectively. The physicochemical interpretation of selected models, indicated the importance of aliphatic substituents at the hydrazone moiety to antifungal activity, corroborating experimental data.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1935321DOI Listing
June 2021

Structure-Based Design of Selective Salt-Inducible Kinase Inhibitors.

J Med Chem 2021 06 4;64(12):8142-8160. Epub 2021 Jun 4.

Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.

Salt-inducible kinases (SIKs) are key metabolic regulators. The imbalance in SIK function is associated with the development of diverse cancers, including breast, gastric, and ovarian cancers. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-]pyrimidin-7-one-based p21-activated kinase (PAK) inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets, MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02144DOI Listing
June 2021

Ligand Accessibility Insights to the Dengue Virus NS3-NS2B Protease Assessed by Long-Timescale Molecular Dynamics Simulations.

ChemMedChem 2021 Aug 18;16(16):2524-2534. Epub 2021 May 18.

Department of Medical Oncology and Pneumology, University Hospital of Tübingen, Otfried-Müller-Strasse 14, 72076, Tübingen, Germany.

Dengue is a tropical disease caused by the dengue virus (DENV), with an estimate of 300 million new cases every year. Due to the limited vaccine efficiency and absence of effective antiviral treatment, new drug candidates are urgently needed. DENV NS3-NS2B protease complex is essential for viral post-translational processing and maturation, and this enzyme has been extensively studied as a relevant drug target. Crystal structures often underestimate NS3-NS2B flexibility, whereas they can adopt different conformational states depending on the bound substrate. We conducted molecular dynamics simulations (∼30 μs) with a non- and covalently bound inhibitor to understand the conformational changes in the DENV-3 NS3-NS2B complex. Our results show that the open-closing movement of the protease exposes multiple druggable subpockets that can be investigated in later drug discovery efforts.
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http://dx.doi.org/10.1002/cmdc.202100246DOI Listing
August 2021

Tetrahydroquinoline/4,5-Dihydroisoxazole Molecular Hybrids as Inhibitors of Breast Cancer Resistance Protein (BCRP/ABCG2).

ChemMedChem 2021 Sep 18;16(17):2686-2694. Epub 2021 May 18.

Faculty of Health Sciences, University of Eastern Finland, Kuopio, 70211, Finland.

Multidrug resistance (MDR) is one of the major factors in the failure of many chemotherapy approaches. In cancer cells, MDR is mainly associated with the expression of ABC transporters such as P-glycoprotein, MRP1 and ABCG2. Despite major efforts to develop new selective and potent inhibitors of ABC drug transporters, no ABCG2-specific inhibitors for clinical use are yet available. Here, we report the evaluation of sixteen tetrahydroquinoline/4,5-dihydroisoxazole derivatives as a new class of ABCG2 inhibitors. The affinity of the five best inhibitors was further investigated by the vanadate-sensitive ATPase assay. Molecular modelling data, proposing a potential binding mode, suggest that they can inhibit the ABCG2 activity by binding on site S1, previously reported as inhibitors binding region, as well targeting site S2, a selective region for substrates, and by specifically interacting with residues Asn436, Gln398, and Leu555. Altogether, this study provided new insights into THQ/4,5-dihydroisoxazole molecular hybrids, generating great potential for the development of novel most potent ABCG2 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100188DOI Listing
September 2021

Structural Characterization of LsrK as a Quorum Sensing Target and a Comparison between X-ray and Homology Models.

J Chem Inf Model 2021 03 8;61(3):1346-1353. Epub 2021 Mar 8.

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

Quorum sensing is being investigated as an alternative therapeutic strategy in antibacterial drug discovery programs aimed at combatting bacterial resistance. LsrK is an autoinducer-2 kinase (belongs to the sugar kinase family), playing a key role in the phosphorylation of the autoinducer-2 (AI-2) signaling molecules involved in quorum sensing. Inhibiting LsrK could result in reduced pathogenicity by interfering with quorum sensing signaling. Previously, we have generated homology models to employ in structure-based virtual screening and successfully identified the first class of LsrK inhibitors. While conducting these studies, the crystal structure of LsrK was released, providing us with an opportunity to evaluate the reliability and quality of our models. A comparative structural analysis of the crystal structure and homology models revealed consistencies among them in the overall structural fold and binding site. Furthermore, the binding characteristics and conformational changes of LsrK have been investigated using molecular dynamics to inspect whether LsrK undergoes similar conformational changes as that of sugar kinases. These studies revealed the flexibility of the LsrK C-terminal domain (Domain II) attributing to the conformational changes in LsrK resulting in open and closed states during the phosphorylation. Further, simulations provided us with insights into the flexibility of a loop in Domain I that can influence the ligand accessibility to the LsrK binding site.
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http://dx.doi.org/10.1021/acs.jcim.0c01233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028047PMC
March 2021

Structure-activity relationship and mechanistic studies for a series of cinnamyl hydroxamate histone deacetylase inhibitors.

Bioorg Med Chem 2021 04 23;35:116085. Epub 2021 Feb 23.

Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address:

Histone deacetylases (HDACs) are a family of enzymes that modulate the acetylation status histones and non-histone proteins. Histone deacetylase inhibitors (HDACis) have emerged as an alternative therapeutic approach for the treatment of several malignancies. Herein, a series of urea-based cinnamyl hydroxamate derivatives is presented as potential anticancer HDACis. In addition, structure-activity relationship (SAR) studies have been performed in order to verify the influence of the linker on the biological profile of the compounds. All tested compounds demonstrated significant antiproliferative effects against solid and hematological human tumor cell lines. Among them, 11b exhibited nanomolar potency against hematological tumor cells including Jurkat and Namalwa, with IC values of 40 and 200 nM, respectively. Cellular and molecular proliferation studies, in presence of compounds 11a-d, showed significant cell growth arrest, apoptosis induction, and up to 43-fold selective cytotoxicity for leukemia cells versus non-tumorigenic cells. Moreover, compounds 11a-d increased acetylated α-tubulin expression levels, which is phenotypically consistent with HDAC inhibition, and indirectly induced DNA damage. In vitro enzymatic assays performed for 11b revealed a potent HDAC6 inhibitory activity (IC: 8.1 nM) and 402-fold selectivity over HDAC1. Regarding SAR analysis, the distance between the hydroxamate moiety and the aromatic ring as well as the presence of the double bond in the cinnamyl linker were the most relevant chemical feature for the antiproliferative activity of the series. Molecular modeling studies suggest that cinnamyl hydroxamate is the best moiety of the series for binding HDAC6 catalytic pocket whereas exploration of Ser568 by the urea connecting unity (CU) might be related with the selectivity observed for the cinnamyl derivatives. In summary, cinnamyl hydroxamate derived compounds with HDAC6 inhibitory activity exhibited cell growth arrest and increased apoptosis, as well as selectivity to acute lymphoblastic leukemia cells. This study explores interesting compounds to fight against neoplastic hematological cells.
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http://dx.doi.org/10.1016/j.bmc.2021.116085DOI Listing
April 2021

Nelfinavir and Its Active Metabolite M8 Are Partial Agonists and Competitive Antagonists of the Human Pregnane X Receptor.

Mol Pharmacol 2021 03 22;99(3):184-196. Epub 2021 Jan 22.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany (O.B., M.S.); Fraunhofer Institute for Molecular Biology and Applied Ecology IME, ScreeningPort, Hamburg, Germany (T.K., O.K., B.W.); Biobank of the Department of General, Visceral, and Transplantion Surgery, University Hospital, Ludwig-Maximilians University, Munich, Munich, Germany (S.M.L.L., T.S.S.); Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany (M.S.); and Department of Chemistry, Institute for Biochemistry and Molecular Biology, Universität Hamburg, Hamburg, Germany (B.W.)

The HIV protease inhibitor nelfinavir is currently being analyzed for repurposing as an anticancer drug for many different cancers because it exerts manifold off-target protein interactions, finally resulting in cancer cell death. Xenosensing pregnane X receptor (PXR), which also participates in the control of cancer cell proliferation and apoptosis, was previously shown to be activated by nelfinavir; however, the exact molecular mechanism is still unknown. The present study addresses the effects of nelfinavir and its major and pharmacologically active metabolite nelfinavir hydroxy--butylamide (M8) on PXR to elucidate the underlying molecular mechanism. Molecular docking suggested direct binding to the PXR ligand-binding domain, which was confirmed experimentally by limited proteolytic digestion and competitive ligand-binding assays. Concentration-response analyses using cellular transactivation assays identified nelfinavir and M8 as partial agonists with EC values of 0.9 and 7.3 µM and competitive antagonists of rifampin-dependent induction with IC values of 7.5 and 25.3 µM, respectively. Antagonism exclusively resulted from binding into the PXR ligand-binding pocket. Impaired coactivator recruitment by nelfinavir as compared with the full agonist rifampin proved to be the underlying mechanism of both effects on PXR. Physiologic relevance of nelfinavir-dependent modulation of PXR activity was investigated in respectively treated primary human hepatocytes, which showed differential induction of PXR target genes and antagonism of rifampin-induced ABCB1 and CYP3A4 gene expression. In conclusion, we elucidate here the molecular mechanism of nelfinavir interaction with PXR. It is hypothesized that modulation of PXR activity may impact the anticancer effects of nelfinavir. SIGNIFICANCE STATEMENT: Nelfinavir, which is being investigated for repurposing as an anticancer medication, is shown here to directly bind to human pregnane X receptor (PXR) and thereby act as a partial agonist and competitive antagonist. Its major metabolite nelfinavir hydroxy--butylamide exerts the same effects, which are based on impaired coactivator recruitment. Nelfinavir anticancer activity may involve modulation of PXR, which itself is discussed as a therapeutic target in cancer therapy and for the reversal of chemoresistance.
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http://dx.doi.org/10.1124/molpharm.120.000116DOI Listing
March 2021

Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol.

Res Social Adm Pharm 2021 07 29;17(7):1347-1355. Epub 2020 Oct 29.

Cruzeiro do Sul University, Sao Paulo, Brazil. Electronic address:

Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide.

Objectives: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH).

Methods: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients.

Summary: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.
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http://dx.doi.org/10.1016/j.sapharm.2020.10.007DOI Listing
July 2021

Improving the solubility of an antifungal thiazolyl hydrazone derivative by cyclodextrin complexation.

Eur J Pharm Sci 2021 Jan 25;156:105575. Epub 2020 Sep 25.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais - Av. Presidente Antônio Carlos, 6627, Campus Pampulha - CEP: 31270-901Belo Horizonte, Minas Gerais - Brasil. Electronic address:

RN104, named 2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole, is a thiazolyl hydrazone derivative with promising antifungal activity. A HPLC-DAD method was carried out using C18 end-capped column (250 × 4.6 mm, 5 µm) and a mobile phase composed of water and acetonitrile (15:85 v/v) at a flow rate of 1.2 mL/min, injection volume 25 μL and DAD detection at 240 nm. The method showed to be selective, linear in the range of 20 to 240 µg/mL, precise, accurate and robust.Due to the low solubility of RN104 in water, the development of inclusion complexes using different cyclodextrins (β-CD, γ-CD and 2-HP-β-CD) was investigated, as well as the interaction mode between RN104 and cyclodextrins using molecular docking followed by semi-empirical calculations. Among tested cyclodextrins, the best results were obtained with 2-HP-β-CD, which promoted an 18-fold increase in RN104's aqueous solubility.
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http://dx.doi.org/10.1016/j.ejps.2020.105575DOI Listing
January 2021

Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors.

Bioorg Med Chem 2020 08 20;28(15):115600. Epub 2020 Jun 20.

Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Faculty of Pharmaceutical Sciences, University of São Paulo, Prof. Lineu Prestes Avenue, 580, Bl.13, São Paulo, SP, Brazil. Electronic address:

The enzyme dihydrofolate reductase from M.tuberculosis (MtDHFR) has a high unexploited potential to be a target for new drugs against tuberculosis (TB), due to its importance for pathogen survival. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototype for analogue development by bioisosterism/retro-bioisosterism, which resulted in 20 new substituted 3-benzoic acid derivatives. Compounds were active against MtDHFR, with IC values ranging from 7 to 40 μM, where compound 4e not only had the best inhibitory activity (IC = 7 μM), but also was 71-fold more active than the original fragment MB872. The 4e inhibition kinetics indicated an uncompetitive mechanism, which was supported by molecular modeling which suggested that the compounds can access an independent backpocket from the substrate and competitive inhibitors. Thus, based on these results, substituted 3-benzoic acid derivatives have strong potential to be developed as novel MtDHFR inhibitors and also anti-TB agents.
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http://dx.doi.org/10.1016/j.bmc.2020.115600DOI Listing
August 2020

The application of machine learning techniques to innovative antibacterial discovery and development.

Expert Opin Drug Discov 2020 10 17;15(10):1165-1180. Epub 2020 Jun 17.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG) , Belo Horizonte, Brazil.

Introduction: After the initial wave of antibiotic discovery, few novel classes of antibiotics have emerged, with the latest dating back to the 1980's. Furthermore, the pace of antibiotic drug discovery is unable to keep up with the increasing prevalence of antibiotic drug resistance. However, the increasing amount of available data promotes the use of machine learning techniques (MLT) in drug discovery projects (. construction of regression/classification models and ranking/virtual screening of compounds).

Areas Covered: In this review, the authors cover some of the applications of MLT in medicinal chemistry, focusing on the development of new antibiotics, the prediction of resistance and its mechanisms. The aim of this review is to illustrate the main advantages and disadvantages and the major trends from studies over the past 5 years.

Expert Opinion: The application of MLT to antibacterial drug discovery can aid the selection of new and potent lead compounds, with desirable pharmacokinetic and toxic profiles for further optimization. The increasing volume of available data along with the constant improvement in computational power and algorithms has meant that we are experiencing a transition in the way we face modern issues such as drug resistance, where our decisions are data-driven and experiments can be focused by data-suggested hypotheses.
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http://dx.doi.org/10.1080/17460441.2020.1776696DOI Listing
October 2020

Molecular Target Validation of Aspartate Transcarbamoylase from by Torin 2.

ACS Infect Dis 2020 05 12;6(5):986-999. Epub 2020 Mar 12.

Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Avenida Professor Lineu Prestes 1374, 05508-000 São Paulo-SP, Brazil.

Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant of ATC (ATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. analyses revealed the potential binding mode of Torin 2 to ATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting ATC as a target of this drug and a promising target for the development of novel antimalarials.
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http://dx.doi.org/10.1021/acsinfecdis.9b00411DOI Listing
May 2020

Inhibition of Porcine Aminopeptidase M (pAMP) by the Pentapeptide Microginins.

Molecules 2019 Nov 29;24(23). Epub 2019 Nov 29.

Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes, 580, Bl. 13, São Paulo/SP CEP 05508-000, Brazil.

Aminopeptidase M (AMP) inhibition is of interest for several diseases, such as highly vascularized cancer types. AMP can be inhibited by linear pentapeptides isolated from LTPNA08 (MG7XX). Porcine AMP inhibition-a model for human AMP-activity was spectrophotometrically measured by the formation of p-nitroanilide from L-leucine-p-nitroanilide substrate by AMP. AMP inhibition by MG770 exhibited comparable inhibition levels to amastatin (IC values: 1.20 ± 0.1 μM and 0.98 ± 0.1 μM, respectively), while MG756 was slightly less potent (with IC values of 3.26 ± 0.5 μM). Molecular modelling suggests a potential binding mode, based on the interaction with the Zn cofactor, where MG770's extra methyl group contributes to the disturbance of the Zn cofactor complex and highlights the importance of hydrophobicity for the site.
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http://dx.doi.org/10.3390/molecules24234369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930480PMC
November 2019

Virtual screening of antibacterial compounds by similarity search of Enoyl-ACP reductase (FabI) inhibitors.

Future Med Chem 2020 01 15;12(1):51-68. Epub 2019 Nov 15.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, Brazil 31270-901.

Antibiotic resistance is an alarming issue, as multidrug-resistant bacteria are growing worldwide, hence the decrease of therapeutic potential of available antibiotic arsenal. Among these bacteria, was pointed by the WHO in the pathogens list to be prioritized in drug development. We report the use of chemical similarity models for the virtual screening of new antibacterial with structural similarity to known inhibitors of FabI. The potential inhibitors were experimentally evaluated for antibacterial activity and membrane disrupting capabilities. These models led to the finding of four new compounds with antibacterial activity, one of which having antimicrobial activity already reported in the literature.
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http://dx.doi.org/10.4155/fmc-2019-0158DOI Listing
January 2020

Ligand- and Structure-Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence.

ChemMedChem 2019 12 7;14(23):1995-2004. Epub 2019 Nov 7.

Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil.

Enoyl-acyl carrier protein reductase (FabI) is the limiting step to complete the elongation cycle in type II fatty acid synthase (FAS) systems and is a relevant target for antibacterial drugs. E. coli FabI has been employed as a model to develop new inhibitors against FAS, especially triclosan and diphenyl ether derivatives. Chemical similarity models (CSM) were used to understand which features were relevant for FabI inhibition. Exhaustive screening of different CSM parameter combinations featured chemical groups, such as the hydroxy group, as relevant to distinguish between active/decoy compounds. Those chemical features can interact with the catalytic Tyr156. Further molecular dynamics simulation of FabI revealed the ionization state as a relevant for ligand stability. Also, our models point the balance between potency and the occupancy of the hydrophobic pocket. This work discusses the strengths and weak points of each technique, highlighting the importance of complementarity among approaches to elucidate EcFabI inhibitor's binding mode and offers insights for future drug discovery.
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http://dx.doi.org/10.1002/cmdc.201900415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916556PMC
December 2019

The inner rod of virulence-associated type III secretion systems constitutes a needle adapter of one helical turn that is deeply integrated into the system's export apparatus.

Mol Microbiol 2019 09 26;112(3):918-931. Epub 2019 Jun 26.

Interfaculty Institute of Microbiology and Infection Medicine (IMIT), University of Tübingen, Elfriede-Aulhorn-Str. 6, Tübingen, 72076, Germany.

Type III secretion injectisomes are essential virulence factors for many pathogenic bacteria by mediating the transport of effector proteins into eukaryotic host cells. The secretion conduit of injectisomes is formed by a helical assembly of three hydrophobic proteins (SctR, SctS and SctT), an inner rod (SctI) and a needle filament (SctF). SctI is thought to play a role in switching between the secretion of different substrate classes and assembly of the inner rod has been implicated in regulating the length of the needle filament. While high-resolution structures of the hydrophobic components and of the needle filament have been solved, little is known about the structure and the assembly of the inner rod, which impedes the deeper assessment of its function. Here we show by exhaustive in vivo photocrosslinking that SctI engages in extensive interactions with SctR and SctT throughout its entire length. Our data imply that the inner rod serves as an adapter between the export apparatus and the needle filament by forming one helical turn. We show that assembly of the inner rod does not play a role in needle length control nor in substrate specificity switching. Instead, our findings imply that inner rod assembly must precede assembly of the needle filament.
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http://dx.doi.org/10.1111/mmi.14327DOI Listing
September 2019

HQSAR and random forest-based QSAR models for anti-T. vaginalis activities of nitroimidazoles derivatives.

J Mol Graph Model 2019 07 19;90:180-191. Epub 2019 Apr 19.

Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG, 31270-901, Brazil. Electronic address:

Trichomonas vaginalis is the causative agent of trichomoniasis, a highly prevalent sexually transmitted infection worldwide. Nitroimidazole drugs, such as metronidazole and tinidazole, are the only recommended treatment, but cases of resistance represent at least 5%. In case of resistance or therapeutic failure, posology with higher doses is used, culminating in the increase of the toxic effects of the treatment. In this context, the development of new drugs becomes an eminent necessity. Hologram quantitative structure-activity relationship (HQSAR) models using nitroimidazole derivatives were generated to discover the relationship between the different chemical structures and the activity against cells and the selectivity against susceptible and resistant strains. One model of each strain was chosen for interpretation, both showed good internal coefficient (q values: 0.607 for susceptible strain and 0.646 for resistant strain subsets) and great values in other internal and external validations metrics. From the contribution of fragments to HQSAR models, several differences between the most and least potent compounds were found: 5-nitroimidazole contributes positively while 4-nitroimidazole negatively. QSAR models employing random forest (RF-QSAR) machine learning technique were also built and a robust model was obtained from resistant strain activity prediction (q equals to 0.618). The constructed HQSAR and RF-QSAR models were employed to predict the activity of three newly planned nitroimidazole derivatives in the design of new drugs candidates against T. vaginalis strains.
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http://dx.doi.org/10.1016/j.jmgm.2019.04.007DOI Listing
July 2019

QSAR studies on the human sirtuin 2 inhibition by non-covalent 7,5,2-anilinobenzamide derivatives.

J Biomol Struct Dyn 2020 02 21;38(2):354-363. Epub 2019 Feb 21.

Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo (USP), Sao Paulo, SP, Brazil.

Sirtuin 2 is a key enzyme in gene expression regulation that is often associated with tumor proliferation control and therefore is a relevant anticancer drug target. Anilinobenzamide derivatives have been discussed as selective sirtuin 2 inhibitors and can be developed further. In the present study, hologram and three-dimensional quantitative structure-activity relationship (HQSAR and 3D-QSAR) analyses were employed for determining structural contributions of a compound series containing human sirtuin-2-selective inhibitors that were then correlated with structural data from the literature. The final QSAR models were robust and predictive according to statistical validation ( and values higher than 0.85 and 0.75, respectively) and could be employed further to generate fragment contribution and contour maps. 3D-QSAR models together with information about the chemical properties of sirtuin 2 inhibitors can be useful for designing novel bioactive ligands.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1574603DOI Listing
February 2020

Antibacterial activity of synthetic 1,3-bis(aryloxy)propan-2-amines against Gram-positive bacteria.

Microbiologyopen 2019 11 17;8(11):e814. Epub 2019 Feb 17.

Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.

Synthetic 1,3-bis(aryloxy)propan-2-amines have been shown in previous studies to possess several biological activities, such as antifungal and antiprotozoal. In the present study, we describe the antibacterial activity of new synthetic 1,3-bis(aryloxy)propan-2-amines against Gram-positive pathogens (Streptococcus pyogenes, Enterococcus faecalis and Staphylococcus aureus) including Methicillin-resistant S. aureus strains. Our compounds showed minimal inhibitory concentrations (MIC) in the range of 2.5-10 μg/ml (5.99-28.58 μM), against different bacterial strains. The minimal bactericidal concentrations found were similar to MIC, suggesting a bactericidal mechanism of action of these compounds. Furthermore, possible molecular targets were suggested by chemical similarity search followed by docking approaches. Our compounds are similar to known ligands targeting the cell division protein FtsZ, Quinolone resistance protein norA and the Enoyl-[acyl-carrier-protein] reductase FabI. Taken together, our data show that synthetic 1,3-bis(aryloxy)propan-2-amines are active against Gram-positive bacteria, including multidrug-resistant strains and can be a promising lead in the development of new antibacterial compounds for the treatment of these infections.
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http://dx.doi.org/10.1002/mbo3.814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855212PMC
November 2019

Advances with support vector machines for novel drug discovery.

Expert Opin Drug Discov 2019 01 29;14(1):23-33. Epub 2018 Nov 29.

c Escola de Artes, Ciências e Humanidades , Universidade de São Paulo (USP) , São Paulo , Brazil.

Introduction: Novel drug discovery remains an enormous challenge, with various computer-aided drug design (CADD) approaches having been widely employed for this purpose. CADD, specifically the commonly used support vector machines (SVMs), can employ machine learning techniques. SVMs and their variations offer numerous drug discovery applications, which range from the classification of substances (as active or inactive) to the construction of regression models and the ranking/virtual screening of databased compounds. Areas covered: Herein, the authors consider some of the applications of SVMs in medicinal chemistry, illustrating their main advantages and disadvantages, as well as trends in their utilization, via the available published literature. The aim of this review is to provide an up-to-date review of the recent applications of SVMs in drug discovery as described by the literature, thereby highlighting their strengths, weaknesses, and future challenges. Expert opinion: Techniques based on SVMs are considered as powerful approaches in early drug discovery. The ability of SVMs to classify active or inactive compounds has enabled the prioritization of substances for virtual screening. Indeed, one of the main advantages of SVMs is related to their potential in the analysis of nonlinear problems. However, despite successes in employing SVMs, the challenges of improving accuracy remain.
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http://dx.doi.org/10.1080/17460441.2019.1549033DOI Listing
January 2019

In vitro and in silico studies of antioxidant activity of 2-thiazolylhydrazone derivatives.

J Mol Graph Model 2019 01 12;86:106-112. Epub 2018 Oct 12.

Department of Pharmaceutical Products, Pharmacy Faculty, Federal University of Minas Gerais, 6627 Antônio Carlos AVE, 31270-901, Belo Horizonte, Minas Gerais, Brazil. Electronic address:

The antioxidant potential of a series of thiazolylhydrazone derivatives was investigated using three different methods namely DPPH, ABTS and FRAP assays. In general, the tested compounds showed higher or comparable activity to that of curcumin, used as positive control. Chemometric analyses demonstrated that the presence of hydrazone moiety is required for the activity of this class of compounds. From these results, compound 4 was identified as the most promising molecule and was then selected for further studies. The antiproliferative effect of compound 4 was evaluated, being active in three (T47D, MDA-MB-231 and SKMEL) of the six cancer cell lines tested, with IC values ranging from 15.9 to 31.3 μM. Compound 4 exhibited no detectable cytotoxic effect on peripheral blood mononuclear cells (PBMC) when tested at a concentration of 100 μM, demonstrating good selectivity. From these results, it is possible to infer that there is a correlation between antioxidant capacity and anticancer effects.
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http://dx.doi.org/10.1016/j.jmgm.2018.10.007DOI Listing
January 2019

Targeting the Plasmodium falciparum plasmepsin V by ligand-based virtual screening.

Chem Biol Drug Des 2019 03 1;93(3):300-312. Epub 2018 Nov 1.

Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.

Malaria is a devastating disease depending only on chemotherapy as treatment. However, medication is losing efficacy, and therefore, there is an urgent need for the discovery of novel pharmaceutics. Recently, plasmepsin V, an aspartic protease anchored in the endoplasmaic reticulum, was demonstrated as responsible for the trafficking of parasite-derived proteins to the erythrocytic surface and further validated as a drug target. In this sense, ligand-based virtual screening has been applied to design inhibitors that target plasmepsin V of P. falciparum (PMV). After screening 5.5 million compounds, four novel plasmepsin inhibitors have been identified which were subsequently analyzed for the potency at the cellular level. Since PMV is membrane-anchored, the verification in vivo by using transgenic PMV overexpressing P. falciparum cells has been performed in order to evaluate drug efficacy. Two lead compounds, revealing IC values were 44.2 and 19.1 μm, have been identified targeting plasmepsin V in vivo and do not significantly affect the cell viability of human cells up to 300 μm. We herein report the use of the consensus of individual virtual screening as a new technique to design new ligands, and we propose two new lead compounds as novel protease inhibitors to target malaria.
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http://dx.doi.org/10.1111/cbdd.13416DOI Listing
March 2019

Molecular Modeling Applied to Nucleic Acid-Based Molecule Development.

Biomolecules 2018 08 27;8(3). Epub 2018 Aug 27.

Unit for Drug Discovery, Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil.

Molecular modeling by means of docking and molecular dynamics (MD) has become an integral part of early drug discovery projects, enabling the screening and enrichment of large libraries of small molecules. In the past decades, special emphasis was drawn to nucleic acid (NA)-based molecules in the fields of therapy, diagnosis, and drug delivery. Research has increased dramatically with the advent of the SELEX (systematic evolution of ligands by exponential enrichment) technique, which results in single-stranded DNA or RNA sequences that bind with high affinity and specificity to their targets. Herein, we discuss the role and contribution of docking and MD to the development and optimization of new nucleic acid-based molecules. This review focuses on the different approaches currently available for molecular modeling applied to NA interaction with proteins. We discuss topics ranging from structure prediction to docking and MD, highlighting their main advantages and limitations and the influence of flexibility on their calculations.
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http://dx.doi.org/10.3390/biom8030083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163985PMC
August 2018

Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles.

Arch Toxicol 2018 Apr 22;92(4):1435-1451. Epub 2018 Jan 22.

Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Schnackenburgallee 114, 22525, Hamburg, Germany.

Activation of pregnane X receptor (PXR) results in the induction of first-pass metabolism and drug efflux. Hereby, PXR may cause adverse drug reactions or therapeutic failure of drugs. PXR inhibition is thus an attractive option to minimise adverse effects or to improve therapeutic efficiencies; however, only a limited number of antagonists have been identified so far. We performed a cell-based high-throughput screen to identify PXR antagonists, using a library of approved and investigational drugs. Two approved drugs, pimecrolimus and pazopanib, emerged as novel potent antagonists of PXR activation, with IC values of 1.2 and 4.1 µM, respectively. We further characterised these with respect to receptor specificity, assembly of the PXR ligand-binding domain (LBD) and interactions with co-factors. In vitro and in silico assays were carried out to identify the site(s) of interaction with the PXR LBD. Primary human hepatocytes were used to investigate antagonism of the induction of endogenous PXR target genes. Pimecrolimus and pazopanib did not affect the transcriptional activity of other nuclear receptors. Both induced the release of co-repressor from PXR and likewise interfered with agonist-induced recruitment of co-activator. Cumulative evidence from cellular and in vitro assays, as well as molecular docking, suggested additional or exclusive binding outside the PXR ligand-binding pocket for both. The compounds differentially antagonised the induction of PXR-regulated genes by rifampicin in primary human hepatocytes. In conclusion, we here have identified two approved drugs as novel potent PXR inhibitors with differential receptor interaction profiles and gene selectivity in primary human hepatocytes.
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http://dx.doi.org/10.1007/s00204-018-2165-4DOI Listing
April 2018

On the relationship of anthranilic derivatives structure and the FXR (Farnesoid X receptor) agonist activity.

J Biomol Struct Dyn 2018 Dec 10;36(16):4378-4391. Epub 2018 Jan 10.

e Department of Pharmaceutical Products, Faculty of Pharmacy , Federal University of Minas Gerais , Belo Horizonte , Minas Gerais , Brazil.

Farnesoid X receptor (FXR) is a nuclear receptor related to lipid and glucose homeostasis and is considered an important molecular target to treatment of metabolic diseases as diabetes, dyslipidemia, and liver cancer. Nowadays, there are several FXR agonists reported in the literature and some of it in clinical trials for liver disorders. Herein, a compound series was employed to generate QSAR models to better understand the structural basis for FXR activation by anthranilic acid derivatives (AADs). Furthermore, here we evaluate the inclusion of the standard deviation (SD) of EC values in QSAR models quality. Comparison between the use of experimental variance plus average values in model construction with the standard method of model generation that considers only the average values was performed. 2D and 3D QSAR models based on the AAD data set including SD values showed similar molecular interpretation maps and quality (Q, Q, and Q), when compared to models based only on average values. SD-based models revealed more accurate predictions for the set of test compounds, with lower mean absolute error indices as well as more residuals near zero. Additionally, the visual interpretation of different QSAR approaches agrees with experimental data, highlighting key elements for understanding the biological activity of AADs. The approach using standard deviation values may offer new possibilities for generating more accurate QSAR models based on available experimental data.
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http://dx.doi.org/10.1080/07391102.2017.1417161DOI Listing
December 2018
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