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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 Open Access Synthesis, anticholinesterase activity and molecular modeling studies of novel carvacrol-substituted amide derivatives(Taylor and Francis Ltd. michael.wagreich@univie.ac.at, 2020) Zengin Kurt, Belma; Durdagi, Serdar; Celebi, Gulsen; Salmas, Ramin Ekhteiari; Sönmez, Fatih; Zengin Kurt, Belma, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Celebi, Gulsen, Department of Pharmacology, Kocaeli Üniversitesi, İzmit, Turkey; Salmas, Ramin Ekhteiari, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Sönmez, Fatih, Pamukova Vocational School, Sakarya University of Applied Sciences, Serdivan, TurkeyIn the present study, 23 novel carvacrol derivatives involving the amide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and tested in vitro as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. 2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide (5v) revealed the highest inhibition properties against AChE and BuChE with the IC50 values of 1.93 and 0.05 µM, respectively. The blood–brain barrier (BBB) permeability of the potent inhibitor (5v) was also assessed by the widely used parallel artificial membrane permeability assay (PAMPA-BBB). The results showed that 5v is capable of crossing the BBB. Pharmacokinetic and toxicity profiles of the studied molecule predictions were investigated by MetaCore/MetaDrug comprehensive systems biology analysis suite. Bioactive conformations of the synthesized molecules, their predicted binding energies as well as structural and dynamical profiles of molecules at the binding pockets of AChE and BuChE targets were also investigated using different docking algorithms and molecular dynamics (MD) simulations. Communicated by Ramaswamy H. Sarma. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Screening of FDA approved drugs for finding potential inhibitors against Granzyme B as a potent drug-repurposing target(Elsevier Inc. usjcs@elsevier.com, 2020) Ikram, Saima; Ahmad, Jamshaid; Durdagi, Serdar; Ikram, Saima, Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Ahmad, Jamshaid, Center of Biotechnology and Microbiology, University of Peshawar, Peshawar, Pakistan; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyGranzyme B is one of the best-characterized and extensively studied member of cytotoxic lymphocytes (CL) proteases. Initially, it is thought to be involved in eliminating virally infected or cancerous cells by using a specialized mechanism through which they are internalized into target cells. In the last decade, however this dimension has changed as there are several reports show that not only CL but also other immune cells can also synthesize Granzyme B. This leads to the possibility of the presence of these proteases in extracellular environment. Being active protease, it then raises the possibility of damaging host tissues as evident from the available reported literature. In many instances, Granzyme B is directly involved in pathogenicity, however in others, it contributes to the disease severity as their over expression makes the clinical situation quite worse which ultimately leads to the chronic state of the disease. Serine protease inhibitor-9 is a natural known intracellular inhibitor of Granzyme B, however there is less data available about the potential inhibitors that can regulate its activity in an extracellular environment. Current study is an effort to identify potential novel inhibitors of Granzyme B. For this aim, drug repurposing study was performed. Around 7900 FDA approved drugs were screened using both ligand- and target-driven approaches. Initially, all molecules were docked using induced fit docking (IFD) approach and selected 318 high-docking scored molecules were used in short (1-ns) molecular dynamics (MD) simulations. Based on MM/GBSA binding free energy calculations, 6 compounds were selected and used in long (100-ns) MD simulations. These compounds were then used in binary QSAR analysis. Therapeutic activity potentials of studied compounds were investigated by Clarivate Analytics's MetaCore/MetaDrug platform which uses binary QSAR models. It is developed based on manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism and toxicity information. Results of selected compounds were compared with a positive control molecule. Current drug repurposing study is a step ahead in finding potential lead compounds by screening database of FDA approved molecules. We have identified novel inhibitors (Tannic acid, Mupirocin, Phytonadiol sodium diphosphate, Cefpiramide, Xenazoic acid) that have potential to decrease the activity of Granzyme B. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Elucidation of interaction mechanism of hERG1 potassium channel with scorpion toxins BeKm-1 and BmTx3b(Elsevier Inc. usjcs@elsevier.com, 2020) Günay, Beril Colak; Yurtsever, Mine; Durdagi, Serdar; Günay, Beril Colak, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Yurtsever, Mine, Department of Chemistry, İstanbul Teknik Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe human ether-a-go-go related gene 1 (hERG1) K+ channels play crucial role in the heart, different regions of brain, endocrine cells, smooth muscle cells, and numerous tumor cells. It is known that the inherited mutations of hERG1 gene may lead to the disorder of cardiac repolarization (i.e., long QT syndrome (LQTS)), which may result in sudden cardiac death. It is known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis and some specific toxins were investigated for diverse therapeutic applications on targeting the hERG1 K+ channel. Thus, investigation of channel/toxin interactions mechanisms in atomic level is an important topic for the development of toxin-based therapeutics. Thus, in this work, the interaction mechanisms of two toxins named as BeKm-1 and BmTx3b with the closed-state hERG1 channel have been studied by using different molecular modeling techniques including protein-protein docking and molecular dynamics (MD) simulations. The crucial residues of toxins in channel interactions have been elucidated. It is found that R1, K6, K18, R20, K23 and R27 residues in BeKm-1 and F1, K7, K19, K20 and K28 in BmTx3b are the important residues involved in the strong interactions with the closed-state hERG1 K+ channel. The results of this study can be used by medicinal chemists in the designing of diverse therapeutic applications of natural or synthetic peptides targeting the closed state hERG1 K+ channels. © 2020 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 Novel AChE and BChE inhibitors using combined virtual screening, text mining and in vitro binding assays(Taylor and Francis Ltd. michael.wagreich@univie.ac.at, 2020) Sahin, Kader; Zengin Kurt, Belma; Sönmez, Fatih; Durdagi, Serdar; Sahin, Kader, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Zengin Kurt, Belma, Department of Pharmaceutical Chemistry, Bezmiâlem Vakıf Üniversitesi, Istanbul, Turkey; Sönmez, Fatih, Pamukova Vocational School, Sakarya University of Applied Sciences, Serdivan, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyIn the current work, we developed a computational pipeline method for predicting the binding affinities of studied compounds at the specific target sites. Since many approved therapeutic compounds involve indole or indole-derivative rings, in the current study we focused compounds including these fingerprints. Initially, 212520 compounds were retrieved from Specs-SC library and after the conversion of IUPAC text file format, compounds that include ‘indol’ keyword (5194 compounds) were used in binary QSAR-based models to screen against a defined therapeutic activity Alzheimer’s disease (AD). The molecules that have higher AD therapeutic activity values (>0.5) were then used in the 26 different toxicity-QSAR models. Binary QSAR models resulted 89 hits that have high AD therapeutic activity and no toxicity. Selected 89 molecules were then screened against acetylcholinesterase (AChE) targets using molecular docking and top-docking poses of compounds were used in initially short (10 ns) molecular dynamics (MD) simulations. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy calculations were performed for 89 ligands and tightly bound 17 ligands based on average MM/GBSA scores were selected for long (100 ns) MD simulations. The same protocol was also applied for the known 4 AChE inhibitors. Selected hits were also docked to the binding pocket of butyrylcholinesterase (BChE). Finally, based on MM/GBSA scores, as well as their corresponding docking scores and metabolite production profiles, 7 compounds were selected and their in vitro tests were performed. Out of 7 compounds, 6 of them showed μM-level inhibition for both AChE and BChE targets. Communicated by Ramaswamy H. Sarma. © 2020 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 In silico characterization of adipokinetic hormone receptor and screening for pesticide candidates against stick insect, Carausius morosus(Elsevier Inc. sinfo-f@elsevier.com, 2020) Birgül İyison, Necla; Sinmaz, Merve Gizem; Duan Şahbaz, Burçin; Shahraki, Aida; Aksoydan, Busecan; Durdagi, Serdar; Birgül İyison, Necla, Department of Molecular Biology and Genetics, Boğaziçi Üniversitesi, Bebek, Turkey; Sinmaz, Merve Gizem, Department of Molecular Biology and Genetics, Boğaziçi Üniversitesi, Bebek, Turkey; Duan Şahbaz, Burçin, Department of Molecular Biology and Genetics, Boğaziçi Üniversitesi, Bebek, Turkey; Shahraki, Aida, Department of Molecular Biology and Genetics, Boğaziçi Üniversitesi, Bebek, Turkey; Aksoydan, Busecan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Neuroscience Program, Bahçeşehir Üniversitesi, Istanbul, TurkeyAdipokinetic hormone (AKH) is an insect neuropeptide that plays crucial roles in a variety of physiological functions such as regulation of heartbeat frequency, blood hemolymph trehalose levels, and protein synthesis. It exerts its functions through binding to its cognate G protein-coupled receptor (GPCR), named adipokinetic hormone receptor (AKHR). The aim of this study is to characterize AKHR of stick insect, Carausius morosus, which becomes an agricultural and forest pest during its outbreaks, and to screen pesticide candidates that would act through inhibition of AKHR. To this aim, the sequence of the receptor and its ligand were obtained from previously published transcriptome data and homology modeling, molecular docking, and molecular dynamics (MD) simulations were combined to find the ligand-binding pocket of AKHR. As a result, crucial residues in ligand binding were identified. These residues were located at the 6th and 7th transmembrane (TM) domains and the 2nd extracellular loop (ECL) of AKHR model. In order to propose pesticide candidates, virtual screening was performed, and candidate ligands were obtained. Considering the binding energies and the stability of the interaction between the ligand and the receptor, four hit compounds were selected. In conclusion, this study revealed a possible ligand-binding pocket of AKHR and proposed some high-affinity small-molecules to block its function, which would further facilitate pesticide design studies against the same receptor of various pests. © 2020 Elsevier B.V., All rights reserved.Publication Metadata only Physics-driven identification of clinically approved and investigation drugs against human neutrophil serine protease 4 (NSP4): A virtual drug repurposing study(Elsevier Inc. sinfo-f@elsevier.com, 2020) Ahmad, Jamshaid; Ikram, Saima; Hafeez, Ahmer Bin; Durdagi, Serdar; Ahmad, Jamshaid, Center of Biotechnology & Microbiology, University of Peshawar, Peshawar, Pakistan; Ikram, Saima, Center of Biotechnology & Microbiology, University of Peshawar, Peshawar, Pakistan, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Hafeez, Ahmer Bin, Center of Biotechnology & Microbiology, University of Peshawar, Peshawar, Pakistan; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, TurkeyNeutrophils synthesize four immune associated serine proteases: Cathepsin G (CTSG), Elastase (ELANE), Proteinase 3 (PRTN3) and Neutrophil Serine Protease 4 (NSP4). While previously considered to be immune modulators, overexpression of neutrophil serine proteases correlates with various disease conditions. Therefore, identifying novel small molecules that can potentially control or inhibit the proteolytic activity of these proteases is crucial to revert or temper the aggravated disease phenotype. To the best of our knowledge, although there is limited data for inhibitors of other neutrophil protease members, there is no previous clinical study of a synthetic small molecule inhibitor targeting NSP4. In this study, an integrated molecular modeling algorithm was performed within a virtual drug repurposing study to identify novel inhibitors for NSP4, using clinically approved and investigation drugs library (∼8000 compounds). Based on our rigorous filtration, we found that following molecules Becatecarin, Iogulamide, Delprostenate and Iralukast are predicted to block the activity of NSP4 by interacting with core catalytic residues. The selected ligands were energetically more favorable compared to the reference molecule. The result of this study identifies promising molecules as potential lead candidates. © 2020 Elsevier B.V., All rights reserved.