SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors

A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery has been witnessed by widespread adoption of these techniques in recent years. Despite great potential, there is a lack of robust and large-scale ML models for discovery of novel SIRT2 inhibitors. In order to support virtual screening (VS), lead optimization, or facilitate the selection of SIRT2 inhibitors for experimental evaluation, a machine-learning-based tool titled SIRT2i_Predictor was developed. The tool was built on a panel of high-quality ML regression and classification-based models for prediction of inhibitor potency and SIRT1-3 isoform selectivity. State-of-the-art ML algorithms were used to train the models on a large and diverse dataset containing 1797 compounds. Benchmarking against structure-based VS protocol indicated comparable coverage of chemical space with great gain in speed. The tool was applied to screen the in-house database of compounds, corroborating the utility in the prioritization of compounds for costly in vitro screening campaigns. The easy-to-use web-based interface makes SIRT2i_Predictor a convenient tool for the wider community. The SIRT2i_Predictor’s source code is made available online

SIRT2i_Predictor: A machine learning-based tool to facilitate the discovery of novel SIRT2 inhibitors

Selective sirtuin 2 (SIRT2) inhibitors hold therapeutic promise for treatment of wide range of age-related diseases. Despite promising preclinical results, none of the SIRT2 inhibitors have reached clinical trials. In order to facilitate development of novel SIRT2 inhibitors, a machine learning based tool titled SIRT2i_Predictor was developed through this work. The main utility of SIRT2i_Predictor is to support virtual screening (VS) campaigns and facilitate the selection of candidates for in vitro and in vivo evaluation. Appealing web-based interface which allows visualization of structure-activity relationships makes SIRT2i_Predictor a valuable tool in the lead optimization projects as well. The tool was built on panel of high-quality machine learning regression-based and binary classification-based models for prediction of inhibitors potency, as well as multiclass classification-based models for predictions of inhibitors SIRT1-3 isoform selectivity. The regression and classification structure-activity relationship models were created for 1797 publicly available compounds by exploring combinations of 5 machine learning algorithms and 4 molecular representations. SIRT2i_Predictor was demonstrated to be able to screen around 200000 compounds in matters of minutes with comparable chemical space coverage to the structure-based VS. The tool was applied in screening of in-house database of compounds further corroborating the utility in prioritization of compounds for costly in vitro screening campaigns. The code of SIRT2i_Predictor is made available at https://github.com/echonemanja/SIRT2i_Predictor

Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs.

Strategies targeting cross-talk between immunosuppressive renal dendritic cells (DCs) and T regulatory cells (Tregs) may be effective in treating cisplatin (CDDP)-induced acute kidney injury (AKI). Galectin 3 (Gal-3), expressed on renal DCs, is known as a crucial regulator of immune response in the kidneys. In this study, we investigated the role of Gal-3 for DCs-mediated expansion of Tregs in the attenuation of CDDP-induced AKI. Methods: AKI was induced in CDDP-treated wild type (WT) C57BL/6 and Gal-3 deficient (Gal-3-/-) mice. Biochemical, histological analysis, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, real-time PCR, magnetic cell sorting, flow cytometry and intracellular staining of renal-infiltrated immune cells were used to determine the differences between CDDP-treated WT and Gal-3-/- mice. Newly synthesized selective inhibitor of Gal-3 (Davanat) was used for pharmacological inhibition of Gal-3. Recombinant Gal-3 was used to demonstrate the effects of exogenously administered soluble Gal-3 on AKI progression. Pam3CSK4 was used for activation of Toll-like receptor (TLR)-2 in DCs. Cyclophosphamide or anti-CD25 antibody were used for the depletion of Tregs. 1-Methyl Tryptophan (1-MT) was used for pharmacological inhibition of Indoleamine 2,3-dioxygenase-1 (IDO1) in TLR-2-primed DCs which were afterwards used in passive transfer experiments. Results: CDDP-induced nephrotoxicity was significantly more aggravated in Gal-3-/- mice. Significantly reduced number of immunosuppressive TLR-2 and IDO1-expressing renal DCs, lower serum levels of KYN, decreased presence of IL-10-producing Tregs and significantly higher number of inflammatory IFN-γ and IL-17-producing neutrophils, Th1 and Th17 cells were observed in the CDDP-injured kidneys of Gal-3-/- mice. Pharmacological inhibitor of Gal-3 aggravated CDDP-induced AKI in WT animals while recombinant Gal-3 attenuated renal injury and inflammation in CDDP-treated Gal-3-/- mice. CDDP-induced apoptosis, driven by Bax and caspase-3, was aggravated in Gal-3-/- animals and in WT mice that received Gal-3 inhibitor (CDDP+Davanat-treated mice). Recombinant Gal-3 managed to completely attenuate CDDP-induced apoptosis in CDDP-injured kidneys of Gal-3-/- mice. Genetic deletion as well as pharmacological inhibition of Gal-3 in renal DCs remarkably reduced TLR-2-dependent activation of IDO1/KYN pathway in these cells diminishing their capacity to prevent transdifferentiation of Tregs in inflammatory Th1 and Th17 cells. Additionally, Tregs generated by Gal-3 deficient DCs were not able to suppress production of IFN-γ and IL-17 in activated neutrophils. TLR-2-primed DCs significantly enhanced capacity of Tregs for attenuation of CDDP-induced AKI and inflammation and expression of Gal-3 on TLR-2-primed DCs was crucially important for their capacity to enhance nephroprotective and immunosuppressive properties of Tregs. Adoptive transfer of TLR-2-primed WTDCs significantly expanded Tregs in the kidneys of CDDP-treated WT and Gal-3-/- recipients resulting in the suppression of IFN-γ and IL-17-driven inflammation and alleviation of AKI. Importantly, this phenomenon was not observed in CDDP-treated WT and Gal-3-/- recipients of TLR-2-primed Gal-3-/-DCs. Gal-3-dependent nephroprotective and immunosuppressive effects of renal DCs was due to the IDO1-induced expansion of renal Tregs since either inhibition of IDO1 activity in TLR-2-primed DCs or depletion of Tregs completely diminished DCs-mediated attenuation of CDDP-induced AKI. Conclusions: Gal-3 protects from CDDP-induced AKI by promoting TLR-2-dependent activation of IDO1/KYN pathway in renal DCs resulting in increased expansion of immunosuppressive Tregs in injured kidneys. Activation of Gal-3:TLR-2:IDO1 pathway in renal DCs should be further explored as new therapeutic approach for DC-based immunosuppression of inflammatory renal diseases

Front Cover: Modulating Proteinâ Protein Interactions with Visibleâ Lightâ Responsive Peptide Backbone Photoswitches (ChemBioChem 11/2019)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149531/1/cbic201900304.pd

Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies

International audienceBackground: Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors

Cardiopulmonary exercise test in the detection of unexplained post-COVID-19 dyspnea: A case report

There is emerging evidence of prolonged recovery in survivors of coronavirus disease 2019 (COVID-19), even in those with mild COVID-19. In this paper, we report a case of a 39-year-old male with excessive body weight and a history of borderline values of arterial hypertension without therapy, who was mainly complaining of progressive dyspnea after being diagnosed with mild COVID-19. According to the recent guidelines on the holistic assessment and management of patients who had COVID-19, all preferred diagnostic procedures, including multidetector computed tomography (CT), CT pulmonary angiogram, and echocardiography, should be conducted. However, in our patient, no underlying cardiopulmonary disorder has been established. Therefore, considering all additional symptoms our patient had beyond dyspnea, our initial differential diagnosis included anxiety-related dysfunctional breathing. However, psychiatric evaluation revealed that our patient had only a mild anxiety level, which was unlikely to provoke somatic complaints. We decided to perform further investiga-tions considering that cardiopulmonary exercise test (CPET) represents a reliable diagnostic tool for patients with unexplained dyspnea. Finally, the CPET elucidated the diastolic dysfunction of the left ventricle, which was the most probable cause of progressive dyspnea in our patient. We suggested that, based on uncontrolled cardiovascular risk factors our patient had, COVID-19 triggered a subclinical form of heart failure (HF) with preserved ejection fraction (HFpEF) to become clinically manifest. Recently, the new onset, exacerbation, or transition from subclinical to clinical HFpEF has been associated with COVID-19. Therefore, in addition to the present literature, our case should warn physicians on HFpEF among survivors of COVID-19

An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

Aims: An infectious disease (COVID-19) caused by the coronavirus SARS-CoV-2 emerged in Wuhan, China in December 2019. Currently, SARS-CoV-2 infected more than 9 million people and caused more than 450 000 deaths. Considering the urgent need for novel therapeutics, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we investigated an integrative in silico drug repurposing approach as a valuable tool for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro).Main methods: To screen FDA-approved drugs, we designed an integrative in silico drug repurposing approach implementing structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data-mining analysis of drug-gene-COVID-19 association.Key findings: Through the presented approach, 43 candidates with potential inhibitory effect on Mpro were selected and further evaluated according to the predictions of tissue disposition, drug-gene-COVID-19 associations and potential pleiotropic effects. We singled out 9 FDA approved drugs as the most promising for their profiling in COVID-19 drug discovery campaigns. Our results were in agreement with current experimental findings, which validate the applied integrative approach and may support clinical decisions for a novel epidemic wave of COVID-19.Significance: To the best of our knowledge, this is the first integrative in silico repurposing study for COVID-19 with a clear advantage in linking structure-based molecular modeling of Mpro inhibitors with predictions of tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.</div

Discovery of 1-benzhydryl piperazine-based HDAC inhibitors with anti-cancer and anti-metastatic properties against human breast cancer: synthesis, molecular modeling, in vitro and in vivo biological evaluation

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors with 1-benzhydryl piperazine as a surface recognition group that differ in hydrocarbon linker. Surprisingly, in vitro HDAC screening identified two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based molecular modelling. The breast cancer cell-lines (MDA-MB-231 and MCF-7) were used to evaluate compound mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities, leading to 8b as the most promising compound. In our study, 8b is identified as the HDAC inhibitor with very potent anti-angiogenic, anti-metastatic and anti-tumor effects in zebrafish MDA-MB-231 xenograft models at low micromolar concentrations

Sacubitril/valsartan in Heart Failure and Beyond—From Molecular Mechanisms to Clinical Relevance

As the ultimate pathophysiological event, heart failure (HF) may arise from various cardiovascular (CV) conditions, including sustained pressure/volume overload of the left ventricle, myocardial infarction or ischemia, and cardiomyopathies. Sacubitril/valsartan (S/V; formerly termed as LCZ696), a first-in-class angiotensin receptor/neprilysin inhibitor, brought a significant shift in the management of HF with reduced ejection fraction by modulating both renin-angiotensin-aldosterone system (angiotensin II type I receptor blockage by valsartan) and natriuretic peptide system (neprilysin inhibition by sacubitril) pathways. Besides, the efficacy of S/V has been also investigated in the setting of other CV pathologies which are during their pathophysiological course and progression deeply interrelated with HF. However, its mechanism of action is not entirely clarified, suggesting other off-target benefits contributing to its cardioprotection. In this review article our goal was to highlight up-to-date clinical and experimental evidence on S/V cardioprotective effects, as well as most discussed molecular mechanisms achieved by this dual-acting compound. Although S/V was extensively investigated in HF patients, additional large studies are needed to elucidate its effects in the setting of other CV conditions. Furthermore, with its antiinflamatory potential, this agent should be investigated in animal models of inflammatory heart diseases, such as myocarditis, while it may possibly improve cardiac dysfunction as well as inflammatory response in this pathophysiological setting. Also, discovering other signalling pathways affected by S/V should be of particular interest for basic researches, while it can provide additional understanding of its cardioprotective mechanisms

Bistable Photoswitch Allows in Vivo Control of Hematopoiesis

Optical control has enabled functional modulation in cell culture with unparalleled spatiotemporal resolution. However, current tools for in vivo manipulation are scarce. Here, we design and implement a genuine on-off optochemical probe capable of achieving hematopoietic control in zebrafish. Our photopharmacological approach first developed conformationally strained visible light photoswitches (CS-VIPs) as inhibitors of the histone methyltransferase MLL1 (KMT2A). In blood homeostasis MLL1 plays a crucial yet controversial role. CS-VIP 8 optimally fulfils the requirements of a true bistable functional system in vivo under visible-light irradiation, and with unprecedented stability. These properties are exemplified via hematopoiesis photoinhibition with a single isomer in zebrafish. The present interdisciplinary study uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, CS-VIP 8 causes MLL1 release with concomitant allosteric rearrangements in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible control without genetic intervention or continuous irradiation, it will foster hematopathology and epigenetic investigations. Furthermore, our workflow will enable exquisite photocontrol over other targets inhibited by macrocycles