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Publication Metadata only Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study(Springer, 2020) Kuskucu, M.; Akyildiz, V.; Kulmány, Ágnes Erika; Ergün, Yavuz; Zencir, Sevil; Zupkó, István; Durdagi, Serdar; Zaka, Mehreen; Sahin, Kader; Orhan, Hande Gürer; Kuskucu, M., Department of Pharmaceutical Biotechnology, Ege Üniversitesi, Izmir, Turkey; Akyildiz, V., Department of Chemistry, Dokuz Eylül Üniversitesi, Izmir, Turkey; Kulmány, Ágnes Erika, Department of Pharmacodynamics and Biopharmacy, University of Szeged Faculty of Pharmacy, Szeged, Hungary; Ergün, Yavuz, Department of Chemistry, Dokuz Eylül Üniversitesi, Izmir, Turkey; Zencir, Sevil, Department of Medical Biology, Pamukkale Üniversitesi, Denizli, Turkey; Zupkó, István, Department of Pharmacodynamics and Biopharmacy, University of Szeged Faculty of Pharmacy, Szeged, Hungary; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Zaka, Mehreen, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Sahin, Kader, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Orhan, Hande Gürer, Department of Pharmacology and Toxicology, Ege Üniversitesi, Izmir, TurkeyThe compounds reducing tumor cell viability and disrupting DNA topoisomerase reactions have been widely used in anticancer drug development. Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is a potent intercalating agent that interferes with nucleic acid processing through interaction with DNA topoisomerase II. Although ellipticine is a well-characterized compound, it is not a widely-accepted drug due to the adverse effects detected upon administration. We have previously reported two novel ellipticine derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2) as potent compounds targeting DNA topoisomerase II. This study covers an extended synthesis, characterization, and activity data for five new salts of N-methyl 5-demetyl ellipticine (Z-1, Z-2, Z-4, Z-5 and Z-6) having several organic halides and their effects on human topoisomerase II enzymes. Moreover, combined in silico studies were conducted for better understanding of modes of action of studied molecules at the binding pocket of target. Our results showed that three of the derivatives (Z-1, Z-2, and Z-6) have considerable effect on the catalytic activity of human topoisomerase II implying the influence of alkyl groups added to the parental structure of ellipticine. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Design, Synthesis, and Molecular Modeling Studies of Novel Coumarin Carboxamide Derivatives as eEF-2K Inhibitors(American Chemical Society, 2020) Comert Onder, Ferah; Durdagi, Serdar; Sahin, Kader; Özpolat, Bülent; Ay, Mehmet; Comert Onder, Ferah, Department of Chemistry, Çanakkale Onsekiz Mart Üniversitesi, Canakkale, Turkey, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Sahin, Kader, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Özpolat, Bülent, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States, Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, United States; Ay, Mehmet, Department of Chemistry, Çanakkale Onsekiz Mart Üniversitesi, Canakkale, TurkeyEukaryotic elongation factor-2 kinase (eEF-2K) is an unusual alpha kinase commonly upregulated in various human cancers, including breast, pancreatic, lung, and brain tumors. We have demonstrated that eEF-2K is relevant to poor prognosis and shorter patient survival in breast and lung cancers and validated it as a molecular target using genetic methods in related in vivo tumor models. Although several eEF-2K inhibitors have been published, none of them have shown to be potent and specific enough for translation into clinical trials. Therefore, development of highly effective novel inhibitors targeting eEF-2K is needed for clinical applications. However, currently, the crystal structure of eEF-2K is not known, limiting the efforts for designing novel inhibitor compounds. Therefore, using homology modeling of eEF-2K, we designed and synthesized novel coumarin-3-carboxamides including compounds A1, A2, and B1-B4 and evaluated their activity by performing in silico analysis and in vitro biological assays in breast cancer cells. The Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) area results showed that A1 and A2 have interaction energies with eEF-2K better than those of B1-B4 compounds. Our in vitro results indicated that compounds A1 and A2 were highly effective in inhibiting eEF-2K at 1.0 and 2.5 μM concentrations compared to compounds B1-B4, supporting the in silico findings. In conclusion, the results of this study suggest that our homology modeling along with in silico analysis may be effectively used to design inhibitors for eEF-2K. Our newly synthesized compounds A1 and A2 may be used as novel eEF-2K inhibitors with potential therapeutic applications. © 2022 Elsevier B.V., All rights reserved.Publication Open Access Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration(Springer, 2020) Sahaboglu, Ayse; Miranda, María; Canjuga, Denis; Avci-Adali, Meltem; Savytska, Natalia; Secer, Enver; Feria Pliego, Jessica Abigail; Kayık, Gülru; Durdagi, Serdar; Sahaboglu, Ayse, Division of Experimental Ophthalmology, Universitätsklinikum und Medizinische Fakultät Tübingen, Tubingen, Germany; Miranda, María, Departamento de Ciencias Biomédicas, Universidad Cardenal Herrera-CEU, Moncada, Spain; Canjuga, Denis, Department of Cardiothoracic Surgery, Universitätsklinikum und Medizinische Fakultät Tübingen, Tubingen, Germany; Avci-Adali, Meltem, Department of Cardiothoracic Surgery, Universitätsklinikum und Medizinische Fakultät Tübingen, Tubingen, Germany; Savytska, Natalia, Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Germany; Secer, Enver, Department of Medical Genetics, Erciyes Üniversitesi, Kayseri, Turkey; Feria Pliego, Jessica Abigail, Universidad Nacional Autónoma de México, Mexico, Mexico; Kayık, Gülru, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division. Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy. Here, we demonstrate and compare the efficacy of two different PARP inhibitors, BMN-673 and 3-aminobenzamide, by using a well-established retinitis pigmentosa model, the rd1 mouse. Moreover, the mechanistic aspects of the PARP inhibitor-induced protection were also investigated in the present study. Our results showed that rd1 rod photoreceptor cell death was decreased by about 25–40% together with the application of these two PARP inhibitors. The wealth of human clinical data available for BMN-673 highlights a strong potential for a rapid clinical translation into novel retinitis pigmentosa treatments. Remarkably, we have found that the efficacy of 3 aminobenzamide was able to decrease PARylation at the nanomolar level. Our data also provide a link between PARP activity with the Wnt/β-catenin pathway and the major intracellular antioxidant concentrations behind the PARP-dependent retinal degeneration. In addition, molecular modeling studies were integrated with experimental studies for better understanding of the role of PARP1 inhibitors in retinal degeneration. © 2020 Elsevier B.V., All rights reserved.Publication Open Access Proposing novel MDM2 inhibitors: Combined physics-driven high-throughput virtual screening and in vitro studies(Blackwell Publishing Ltd, 2020) Aydin, Gulsah; Paksoy, Maide Nur; Orhan, Müge Didem; Avşar, Timuçin; Yurtsever, Mine; Durdagi, Serdar; Aydin, Gulsah, Traditional and Complementary Medicine Applied and Research Center, Düzce Üniversitesi, Duzce, Turkey, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Paksoy, Maide Nur, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Orhan, Müge Didem, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Avşar, Timuçin, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe mouse double minute 2 (MDM2) protein acts as a negative regulator of the p53 tumor suppressor. It directly binds to the N terminus of p53 and promotes p53 ubiquitination and degradation. Since the most common p53-suppressing mechanisms involve the MDM2, proposing novel inhibitors has been the focus of many in silico and also experimental studies. Thus, here we screened around 500,000 small organic molecules from Enamine database at the binding pocket of this oncogenic target. The screening was achieved systematically with starting from the high-throughput virtual screening method followed by more sophisticated docking approaches. The initial high number of screened molecules was reduced to 100 hits which then were studied extensively for their therapeutic activity and pharmacokinetic properties using binary QSAR models. The structural and dynamical profiles of the selected molecules at the binding pocket of the target were studied thoroughly by all-atom molecular dynamics simulations. The free energy of the binding of the hit molecules was estimated by the MM/GBSA method. Based on docking simulations, binary QSAR model results, and free energy calculations, 11 compounds (E1–E11) were selected for in vitro studies. HUVEC vascular endothelium, colon cancer, and breast cancer cell lines were used for testing the binding affinities of the identified hits and for further cellular effects on human cancer cell. Based on in vitro studies, six compounds (E1, E2, E5, E6, E9, and E11) in breast cancer cell lines and six compounds (E1, E2, E5, E6, E8, and E10) in colon cancer cell lines were found as active. Our results showed that these compounds inhibit proliferation and lead to apoptosis. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Integrated Binary QSAR-Driven Virtual Screening and in Vitro Studies for Finding Novel hMAO-B-Selective Inhibitors(American Chemical Society, 2020) İş, Yusuf Serhat; Aksoydan, Busecan; Şentürk, Murat; Yurtsever, Mine; Durdagi, Serdar; İş, Yusuf Serhat, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Department of Chemical Technology, Gedik Üniversitesi, Istanbul, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Şentürk, Murat, Department of Biochemistry, Aǧrı İbrahim Çeçen Üniversitesi, Agri, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey, Virtual Drug Screening and Development Laboratory, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe increased activity of monoamine oxidase (MAO) enzymes may lead to serious consequences since they reduce the level of neurotransmitters and are associated with severe neurodegenerative diseases. The inhibition of this enzyme, especially the B isoform, plays a vital role in the treatment of Parkinson's disease (PD). This study is aimed to find novel human MAO-B (hMAO-B) selective inhibitors. A total of 256.750 compounds from the Otava small molecules database were virtually screened gradually by employing several screening techniques for this purpose. Initially, a high-throughput virtual screening (HTVS) method was employed, and 10% of the molecules having high docking scores were subjected to binary QSAR models for further screening of their therapeutic activities against PD, Alzheimer's disease (AD), and depression as well as for their toxicity and pharmacokinetic properties. Then, enzyme selectivity of the ligands towards the A and B forms that passed through all the filters were studied using the induced-fit docking method and molecular dynamics simulations. At the end of this exhaustive research, we identified two hit molecules ligand 3 (Otava ID: 7131545) and ligand 4 (Otava ID: 7566820). Based on the in vitro results, these two compounds (ligands 3 and 4) together with ligands 1 and 2 found in our previous study showed activity at the nanomolar (nM) level, and the results indicated that these four ligands inhibit hMAO-B better than the FDA-approved drug selegiline. © 2022 Elsevier B.V., All rights reserved.Publication Metadata only Formation of the inclusion complex of water soluble fluorescent calix[4]arene and naringenin: solubility, cytotoxic effect and molecular modeling studies(Taylor and Francis Ltd. michael.wagreich@univie.ac.at, 2020) Oğuz, Mehmet; Bhatti, Asif Ali; Doğan, Berna; Karakurt, Serdar; Durdagi, Serdar; Yilmaz, M.; Oğuz, Mehmet, Department of Chemistry, Selçuk Üniversitesi, Selçuklu, Turkey, Department of Nanotechnology and Advanced Materials, Selçuk Üniversitesi, Selçuklu, Turkey; Bhatti, Asif Ali, Department of Chemistry, Selçuk Üniversitesi, Selçuklu, Turkey, Department of Chemistry, Government College University Hyderabad, Hyderabad, Pakistan; Doğan, Berna, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Karakurt, Serdar, Department of Biochemistry, Selçuk Üniversitesi, Selçuklu, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yilmaz, M., Department of Chemistry, Selçuk Üniversitesi, Selçuklu, TurkeyNaringenin is considered as an important flavonoid in phytochemistry because of its important effect on cancer chemoprevention. Unfortunately its poor solubility has restricted its therapeutic applications. In this study, an efficient water-soluble fluorescent calix[4]arene (compound 5) was synthesized as host macromolecule to increase solubility and cytotoxicity in cancer cells of water-insoluble naringenin as well as to clarify localization of naringenin into the cells. Complex formed by host–guest interaction between compound 5 and naringenin was analyzed with UV–visible, fluorescence, FTIR spectroscopic techniques and molecular modeling studies. Stern–Volmer analysis showed binding constant value of Ksv 3.5 × 107 M−1 suggesting strong interaction between host and guest. Binding capacity shows 77% of naringenin was loaded on compound 5. Anticarcinogenic effects of naringenin complex were evaluated on human colorectal carcinoma cells (DLD-1) and it was found that 5-naringenin complex inhibits proliferation of DLD-1 cells 3.4-fold more compared to free naringenin. Fluorescence imaging studies show 5-naringenin complex was accumulated into the cytoplasm instead of the nucleus. Increased solubility and cytotoxicity of naringenin with fluorescent calix[4]arene makes it one of the potential candidates as a therapeutic enhancer. For deep understanding of host–guest interaction mechanisms, complementary multiscale molecular modeling studies were also carried out. Communicated by Ramaswamy H. Sarma. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Drug Re-positioning Studies for Novel HIV-1 Inhibitors Using Binary QSAR Models and Multi-target-driven In Silico Studies(Wiley-VCH Verlag, 2021) Doğan, Berna; Durdagi, Serdar; Doğan, Berna, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyCurrent antiretroviral therapies against HIV involve the usage of at least two drugs that target different stages of HIV life cycle. However, potential drug interactions and side effects pose a problem. A promising concept for complex disease treatment is ‘one molecule-multiple target’ approach to overcome undesired effects of multiple drugs. Additionally, it is beneficial to consider drug re-purposing due to the cost of taking a drug into the market. Taking these into account, here potential anti-HIV compounds are suggested by virtually screening small approved drug molecules and clinical candidates. Initially, binary QSAR models are used to predict the therapeutic activity of around 7900 compounds against HIV and to predict the toxicity of molecules with high therapeutic activities. Selected compounds are considered for molecular docking studies against two targets, HIV-1 protease enzyme, and chemokine co-receptor CCR5. The top docking poses for all 549 molecules are then subjected to short (1 ns) individual molecular dynamics (MD) simulations and they are ranked based on their calculated relative binding free energies. Finally, 25 molecules are selected for long (200 ns) MD simulations, and 5 molecules are suggested as promising multi-target HIV agents. The results of this study may open new avenues for the designing of new dual HIV-1 inhibitor scaffolds. © 2023 Elsevier B.V., All rights reserved.Publication Metadata only An Integrated in silico Approach and in vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies(John Wiley and Sons Ltd, 2021) Kanan, Duaa; Kanan, Tarek; Doğan, Berna; Orhan, Müge Didem; Avşar, Timuçin; Durdagi, Serdar; Kanan, Duaa, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kanan, Tarek, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Doğan, Berna, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Orhan, Müge Didem, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Avşar, Timuçin, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Biology, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field. © 2021 Elsevier B.V., All rights reserved.Publication Metadata only Screening of small molecule libraries using combined text mining, ligand- and target-driven based approaches for identification of novel granzyme H inhibitors(Elsevier Inc., 2021) Ikram, Saima; Ahmad, Fawad; Ahmad, Jamshaid; Durdagi, Serdar; Ikram, Saima, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan; Ahmad, Fawad, Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan; Ahmad, Jamshaid, Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyGranzymes are serine proteases synthesized by CTL and NK cells. Five granzyme genes (GzmA, -B, -H, -K, -M) are present in humans, which are located at three different chromosomal loci. Being serine proteases, the binding pocket constitutes a catalytic triad (i.e., His59, Asp103 and Ser197). Granzymes are released into target (cancerous and virally infected) cells by a specialized process known as granule exocytosis pathway. After internalization, these proteases initiate apoptosis. Granzymes are also involved in other non-apoptotic immune associated roles like ECM remodeling, cytokine modulation, killing of pathogens through generation of phagosomes. Their intracellular activity is regulated by specialized inhibitors knows as SERPINs. However, if these proteases are secreted in excess into the extracellular environment, their regulation becomes important as otherwise they start self-damage to the tissues thereby worsening the disease conditions. Efforts are being made to identify potential inhibitors for regulation of these proteases in an extracellular environment. Physiological and synthetic inhibitors have been reported against some members however there is no known inhibitor against extracellular human GzmH. Thus, in the current study, we investigated small molecule databases for the identification of potential molecules having the ability to inhibit GzmH by combined molecular simulations, which can ultimately be used as a potential therapeutic agent. © 2021 Elsevier B.V., All rights reserved.Publication Metadata only Identification of first-in-class plasmodium OTU inhibitors with potent anti-malarial activity(Portland Press Ltd, 2021) Siyah, Pinar; Akgol, Sezer; Durdagi, Serdar; Kocabas, Fatih; Siyah, Pinar, Regenerative Biology Research Laboratory, Yeditepe University, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Akgol, Sezer, Regenerative Biology Research Laboratory, Yeditepe University, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Kocabas, Fatih, Regenerative Biology Research Laboratory, Yeditepe University, Istanbul, TurkeyOTU proteases antagonize the cellular defense in the host cells and involve in pathogenesis. Intriguingly, P. falciparum, P. vivax, and P. yoelii have an uncharacterized and highly conserved viral OTU-like proteins. However, their structure, function or inhibitors have not been previously reported. To this end, we have performed structural modeling, small molecule screening, deconjugation assays to characterize and develop first-in-class inhibitors of P. falciparum, P. vivax, and P. yoelii OTU-like proteins. These Plasmodium OTU-like proteins have highly conserved residues in the catalytic and inhibition pockets similar to viral OTU proteins. Plasmodium OTU proteins demonstrated Ubiquitin and ISG15 deconjugation activities as evident by intracellular ubiquitinated protein content analyzed by western blot and flow cytometry. We screened a library of small molecules to determine plasmodium OTU inhibitors with potent anti-malarial activity. Enrichment and correlation studies identified structurally similar molecules. We have identified two small molecules that inhibit P. falciparum, P. vivax, and P. yoelii OTU proteins (IC50 values as low as 30 nM) with potent anti-malarial activity (IC50 of 4.1-6.5 mM). We also established enzyme kinetics, druglikeness, ADME, and QSAR model. MD simulations allowed us to resolve how inhibitors interacted with plasmodium OTU proteins. These findings suggest that targeting malarial OTU-like proteases is a plausible strategy to develop new anti-malarial therapies. © 2022 Elsevier B.V., All rights reserved.