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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 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.Publication Metadata only Drug design of new therapeutic agents: molecular docking, molecular dynamics simulation, DFT and POM analyses of new Schiff base ligands and impact of substituents on bioactivity of their potential antifungal pharmacophore site(Taylor and Francis Ltd., 2023) Akkoç, Senem; Karataş, Halis; Muhammed, Muhammed Tilahun; Kökbudak, Zülbiye; Ceylan, Ahmet Bahattin; Almalki, Faisal A.; Laaroussi, Hamid; Ben hadda, T.; Akkoç, Senem, Department of Basic Sciences, Süleyman Demirel Üniversitesi, Isparta, Turkey, Faculty of Engineering and Natural Sciences, Bahçeşehir Üniversitesi, Istanbul, Turkey; Karataş, Halis, Department of Chemistry, Erciyes Üniversitesi, Kayseri, Turkey; Muhammed, Muhammed Tilahun, Department of Pharmaceutical Chemistry, Süleyman Demirel Üniversitesi, Isparta, Turkey; Kökbudak, Zülbiye, Department of Chemistry, Erciyes Üniversitesi, Kayseri, Turkey; Ceylan, Ahmet Bahattin, Department of Pharmaceutical Biotechnology, Erciyes Üniversitesi, Kayseri, Turkey; Almalki, Faisal A., Department of Pharmaceutical Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia; Laaroussi, Hamid, Laboratory of Applied Chemistry and Environment, Université Mohammed Premier Oujda, Oujda, Morocco; Ben hadda, T., Department of Pharmaceutical Chemistry, Umm Al-Qura University, Makkah, Saudi Arabia, Laboratory of Applied Chemistry and Environment, Université Mohammed Premier Oujda, Oujda, MoroccoSince Schiff base derivatives have a wide range of biological activities, novel Schiff base derivatives were designed and synthesized in satisfactory yields. 1H NMR, 13C NMR, IR, mass and elemental analysis were used to provide a complete structural characterization of the new synthesized Schiff bases (3–6). The antiproliferative activity properties of compounds were tested against two human cancer cell lines including breast (MDA-MB-231) and colon (DLD-1). The compounds overall did not show high cytotoxic activity against both cancer cell lines compared to the positive control drug cisplatin. The synthesized Schiff base compounds were further screened for their in vitro antimicrobial activities against five bacterial strains (Escherichia coli (ATTC 25922), Salmonella thyphimurium (ATTC 14028), Staphylococcus aureus (ATCC 25923), Bacillus subtilis (ATCC 6633), Bacillus cereus (ATCC 11778)) and two fungal strains (Candida albicans (ATCC 10231) and Candida glabrata (ATCC 90030)) using broth micro dilution techniques. The mode of action for the antimicrobial effect in the experimental part was explored through molecular docking. The stability of target-ligand complexes obtained from the docking were assessed through molecular dynamics simulation. The binding affinity of the compounds toward the target protein were also investigated using MMPBSA. Furthermore, electrochemical properties of some compounds was analyzed by DFT calculations. By using POM theory, it becomes more easy to control the bioactivity of drugs. Here, how the physicochemical properties play a crucial role in the orientation of their bioactivity was demonstrated. Communicated by Ramaswamy H. Sarma. © 2023 Elsevier B.V., All rights reserved.Publication Metadata only Density functional modeling, and molecular docking with SARS-CoV-2 spike protein (Wuhan) and omicron S protein (variant) studies of new heterocyclic compounds including a pyrazoline nucleus(Taylor and Francis Ltd., 2023) Akman, Soner; Akkoç, Senem; Zeyrek, Celal Tuǧrul; Muhammed, Muhammed Tilahun; Ilhan, Ilhan Özer; Akman, Soner, Department of Chemistry, Erciyes Üniversitesi, Kayseri, Turkey; Akkoç, Senem, Department of Basic Sciences, Süleyman Demirel Üniversitesi, Isparta, Turkey, Faculty of Engineering and Natural Sciences, Bahçeşehir Üniversitesi, Istanbul, Turkey; Zeyrek, Celal Tuǧrul, Department of Medical Services and Techniques, Çankiri Karatekin Üniversitesi, Cankiri, Turkey; Muhammed, Muhammed Tilahun, Department of Pharmaceutical Chemistry, Süleyman Demirel Üniversitesi, Isparta, Turkey; Ilhan, Ilhan Özer, Department of Chemistry, Erciyes Üniversitesi, Kayseri, TurkeyNowadays, different vaccines and antiviral drugs have been developed and their effectiveness has been proven against SARS-CoV-2. Pyrazoline derivatives are biologically active molecules and exhibit broad-spectrum biological activity properties. In this scope, four new molecules (4a–d) including a pyrazoline core were synthesized in order to predict their antiviral properties theoretically. Compounds 4a–d were purified by the crystallization method. The structures of 4a–d were completely characterized by NMR, IR, and elemental analysis. The molecular structures of the compounds in the ground state have been optimized using density functional theory with the B3LYP/6-31++G(d,p) level. The quantum chemical parameters were predicted by density functional theory calculations. Moreover, the molecular docking studies of 4a–d with SARS-CoV-2 Spike protein (Wuhan) and omicron S protein (variant) were presented to investigate and predict potential interactions. The binding sites, binding types and energies, bond distances of the non-covalent interactions and calculated inhibition constants (calc. Ki) as a consequence of molecular docking for 4a–d were presented in this study. Furthermore, the stability of the protein-4a complex obtained from the docking was investigated through molecular dynamics simulation. Communicated by Ramaswamy H. Sarma. © 2023 Elsevier B.V., All rights reserved.Publication Metadata only Ab initio and comparative 3D modeling of FAM222A-encoded protein and target-driven-based virtual screening for the identification of novel therapeutics against Alzheimer's disease(Elsevier Inc., 2023) Alabdulraheem, Zeyad Tareq Jasim; Durdagi, Serdar; Alabdulraheem, Zeyad Tareq Jasim, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey; Durdagi, Serdar, Department of Biophysics, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Pharmaceutical Chemistry, Bahçeşehir Üniversitesi, Istanbul, Turkey, Bahçeşehir Üniversitesi, Istanbul, TurkeyThe complex nature of Alzheimer's disease (AD) makes it difficult to understand the exact molecular processes leading to neuron death. However, two molecular factors - the production of amyloid-beta plaques and tau tangles - are considered to be linked to AD. A genetic marker for brain atrophy, FAM222A, has been identified by the unique cross-phenotype meta-analysis of genetics imaging and the molecular features show an interaction between the protein aggregatin encoded by FAM222A and amyloid beta (Aβ)-peptide (1-42) via its N-terminal Aβ binding domain, thus increasing Aβ aggregation. Function of Aggregatin protein is unclear, and its 3D structure has not been investigated in experimental analysis, so far. Hence, in the present study, first time in literature, 3D models of FAM222A-encoded Aggregatin were systematically constructed by applying diverse homology modeling approaches and they were used as target structures at the virtual screening of FDA-approved drugs and drugs currently under research in clinical trials. Then, the identified hit molecules were chosen for further molecular dynamics (MD) simulations and post-MD analyses. Our integrated ligand-based and protein-driven-based virtual screening results show that Cefpiramide, Diniprofylline, Fostriecin, and Droperidol may target Aggregatin. © 2023 Elsevier B.V., All rights reserved.Publication Metadata only Investigating the effect of external heat flux on the thermal behaviour of hybrid paraffin-air heat sink: A molecular dynamics approach(Elsevier Ltd, 2023) Wang, Ke; Jasim, Dehyaa J.; Alizadeh, As'ad; Al-Rubaye, Ameer H.; Nasajpour-Esfahani, Navid; Salahshour, Soheil; Esmaeili, Shadi; Hekmatifar, Maboud; Wang, Ke, Guangling College, Yangzhou University, Yangzhou, China; Jasim, Dehyaa J., Department of Petroleum Engineering, Al-Amarah University College, Amarah, Iraq; Alizadeh, As'ad, Department of Civil Engineering, Cihan University-Erbil, Erbil, Iraq; Al-Rubaye, Ameer H., Department of Petroleum Engineering, Al-Kitab University, Kirkuk, Iraq; Nasajpour-Esfahani, Navid, College of Engineering, Atlanta, United States; Salahshour, Soheil, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Tuzla, Turkey, Faculty of Engineering and Natural Sciences, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Mathematics and Computer Science, Lebanese American University, Beirut, Lebanon; Esmaeili, Shadi, Faculty of Physics, Semnan University, Semnan, Iran; Hekmatifar, Maboud, Department of Mechanical Engineering, Islamic Azad University, Tehran, IranOne of today's concerns regarding energy storage units is the low rate of storage and release of thermal energy and, as a result, the efficiency loss in these units. Subsequently, different strategies are utilized to solve this concern, such as using phase change materials (PCMs) and nanostructures. The background is the low storage and release rate of thermal energy in energy storage units, which leads to efficiency loss. This issue concerns many applications, including energy storage in buildings, vehicles, and electronic devices. This study aims to investigate the effect of external heat flux (EHF) on the thermal efficiency of a specific heat sink by employing molecular dynamics (MD) simulation. After ensuring the simulated atomic structures are stable, EHF is applied to see how it affects the thermal behaviour of the combination. The obtained results show that by increasing the EHF applied to the prototype, the thermal behaviour of the structure improves. So, with the increase of EHF from 0.1 W/m2 to 0.5 W/m2, the heat flux and thermal conductivity (TC) increase from 212.27 W/m2 to 317.90 W/mK to 286.71 W/m2 and 340.03 W/mK. The findings significantly affect energy storage unit efficiency and can inform future research and development efforts. © 2023 Elsevier B.V., All rights reserved.Publication Metadata only A numerical study of carbon doping effect on paraffin-reinforced silica aerogel mechanical properties: A molecular dynamics approach(Elsevier B.V., 2023) Zhang, Wei; Jasim, Dehyaa J.; Alizadeh, As'ad; Nasajpour-Esfahani, Navid; Hekmatifar, Maboud; Sabetvand, Roozbeh; Salahshour, Soheil; Toghraie, Davood; Zhang, Wei, Mechanical Engineering, Xi'an Jiaotong University, Xi'an, China; Jasim, Dehyaa J., Department of Petroleum Engineering, Al-Amarah University College, Amarah, Iraq; Alizadeh, As'ad, Department of Civil Engineering, Cihan University-Erbil, Erbil, Iraq; Nasajpour-Esfahani, Navid, College of Engineering, Atlanta, United States; Hekmatifar, Maboud, Department of Mechanical Engineering, Islamic Azad University, Tehran, Iran; Sabetvand, Roozbeh, Department of Energy Engineering and Physics, Amirkabir University of Technology, Tehran, Iran; Salahshour, Soheil, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Tuzla, Turkey, Faculty of Engineering and Natural Sciences, Bahçeşehir Üniversitesi, Istanbul, Turkey, Department of Mathematics and Computer Science, Lebanese American University, Beirut, Lebanon; Toghraie, Davood, Department of Mechanical Engineering, Islamic Azad University, Tehran, IranAerogels are different types of porous and solid materials that exhibit a strange set of extraordinary material properties. Aerogels have great potential for use in the fields of heat, sound, electronics, and especially thermal insulation. This paper investigates the influence of carbon doping concentration on the mechanical properties of paraffin-reinforced silica aerogel (PRSA). To do this investigation, Young's module (YM), stress–strain curve, and ultimate strength (US) values at various carbon-doped particles of 1 to 10 % were reported by molecular dynamics (MD) simulation. The results show that the PRSA, under the influence of carbon doping, has dual performance. To be more precise, by adding the amount of carbon doped from 1 to 3 %, the US and YM of the PRSA rose from 329.96 and 1137.20 MPa to 353.73 and 1268.44 MPa. In other words, the mechanical strength of the PRSA increases in a limited ratio. However, by increasing carbon doping from 3 to 10 %, the US and YM of the PRSA reduced to 306.233 and 1041.88 MPa, respectively. So, it is expected that the mechanical behavior of the PRSA matrix to be manipulated with carbon doping for actual applications. © 2023 Elsevier B.V., All rights reserved.