Life Sciences Commons^™

Non-Small Cell Lung Cancer Treatment: Current Status Of Drug Repurposing And Nanoparticle-Based Drug Delivery Systems, Tugba Gul Inci, Serap Acar, Di̇lek Balik

Turkish Journal of Biology

Drug repurposing is the strategy of drug utilization for a treatment option other than the intended indications and has increased over the past decades, especially within cancer nanomedicine. Cancer nanomedicine has been facilitated through nanoparticle-based (NP-based) delivery systems which can combat NSCLC via recent advances in nanotechnology and apply its benefits to existing drugs. An effective therapeutic solution could be gained via repurposing and accelerated via NP-based drug delivery systems. This review aims to present an overview of NSCLC treatments with a special focus on drug repurposing with details of clinical study advances and NP-based drug delivery systems for NSCLC. …

Repurposing Of Us-Fda-Approved Drugs As Negative Modulators Of Ubiquitin Specific Protease-7 (Usp7), Seema Zadi, Sumaira Javaid, Atia-Tul-Wahab, Humaira Zafar, Muhammad Awais, Innokentiy Maslennikov, M. Iqbal Choudhary

Pharmacy Faculty Articles and Research

Ubiquitin-specific protease7 (USP7) regulates the stability of the p53 tumor suppressor protein and several other proteins critical for tumor cell survival. Aberrant expression of USP7 facilitates human malignancies by altering the activity of proto-oncogenes/proteins, and tumor suppressor genes. Therefore, USP7 is a validated anti-cancer drug target. In this study, a drug repurposing approach was used to identify new hits against the USP7 enzyme. It is one of the most strategic approaches to find new uses for drugs in a cost- and time-effective way. Nuclear Magnetic Resonance-based screening of 172 drugs identified 11 compounds that bind to the catalytic domain of …

Computational Molecular Docking Studies Of Small Molecule Inhibitors With The Sars-Cov-2 Spike Protein Variants: In-Silico Drug Discovery Using Virtual Screening And Drug Repurposing Approaches, Grace Gupta

Computational and Data Sciences (MS) Theses

The pandemic caused by the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has caused a global public health crisis of nearly unprecedented scale. In the years following the outbreak, the scientific community has mobilized to develop several vaccines and treatments. Drug repurposing as a strategy for drug development has produced many of the current therapeutic options. The greatest challenge to designing a therapeutic inhibitor of SARS-CoV-2 is the shifting mutational landscape of the virus as it evolves. In this study, we focus on the spike protein as a target for potential inhibitors. We explore two …

Drug Repurposing Using Gene Expression Data Mining, Yue Qiu

Dissertations, Theses, and Capstone Projects

The conventional drug discovery process that employs the "one disease, one target, one drug'' paradigm is expensive, time-consuming, and has a high rate of failure for multi-genic complex diseases. An alternative approach to drug discovery is to repurpose an existing drug that has been used to treat some medical conditions. Drug repurposing is considered a promising method due to its accelerated the process of drug discovery and lower overall cost and risk.

Drug-perturbed gene expression profiles are powerful phenotype readouts of biological systems, and they have been widely used in drug repurposing studies. However, the existing drug-perturbed gene expression datasets …

Cryogenic X-Ray Crystallographic Studies Of Biomacromolecules At Turkish Light Source "Turkish Delight", Necati̇ Atalay, Enver Kami̇l Akcan, Mehmet Gül, Esra Ayan, Ebru Destan, Fatma Betül Ertem Kuzucu, Nuretti̇n Tokay, Bariş Çakilkaya, Zeli̇ş Nergi̇z, Gözde Karakadioğlu Usta, Abdullah Kepceoğlu, İlki̇n Yapici, Bi̇lge Tosun, Ni̇lüfer Baldir, Günseli̇ Yildirim, J Austin Johnson, Ömür Güven, Alaleh Shafiei, Nazli Eylül Arslan, Merve Yilmaz, Cahi̇ne Kulakman, Seyi̇de Seda Paydos, Seynep Sena Çi̇nal, Kardelen Şabanoğlu, Ayşegül Pazarçevi̇ren, Ayşenur Yilmaz, Başak Canbay, Bengi̇su Aşçi, Esra Kartal, Serra Tavli, Mehmet Çaliseki̇, Günce Göç, Ari̇f Mermer, Gamze Yeşi̇lay, Sevde Altuntaş, Hiroshi Tateishi, Masami Otsuka, Mikako Fujita, Şaban Teki̇n, Hali̇li̇brahi̇m Çi̇ftçi̇, Serdar Durdaği, Gi̇zem Di̇nler Doğanay, Ezgi̇ Karaca, Burcu Kaplan Türköz, Burak Veli̇ Kabasakal, Ahmet Kati, Hasan Demi̇rci̇

Turkish Journal of Biology

X-ray crystallography is a robust and powerful structural biology technique that provides high-resolution atomic structures of biomacromolecules. Scientists use this technique to unravel mechanistic and structural details of biological macromolecules (e.g., proteins, nucleic acids, protein complexes, protein-nucleic acid complexes, or large biological compartments). Since its inception, single-crystal cryocrystallography has never been performed in Türkiye due to the lack of a single-crystal X-ray diffractometer. The X-ray diffraction facility recently established at the University of Health Sciences, İstanbul, Türkiye will enable Turkish and international researchers to easily perform high-resolution structural analysis of biomacromolecules from single crystals. Here, we describe the technical and …

Sars-Cov-2 Main Protease Inhibitors Repurposed For Hiv-1 Protease Binding, Jacob Minkkinen

CSB and SJU Distinguished Thesis

Severe acute respiratory syndrome (SARS-CoV-2) led to the COVID-19 global pandemic, with over 460 million cases of infection and over 6 million deaths since the start of the pandemic. SARS-CoV-2 is a retrovirus that utilizes a main protease (Mpro). Mpro is a catalytic cys/his protease. Several treatments were proposed to stop the pandemic including repurposing drugs to inhibit the Mpro. Another retrovirus that uses a protease is human immunodeficiency virus (HIV-1) which has been a global epidemic for 40 years and is a devastating disease that attacks the immune system. HIV-1 has infected 79.5 million people and has killed an …

Repurposing Lansoprazole And Posaconazole To Treat Leishmaniasis: Integration Of In Vitro Testing, Pharmacological Corroboration, And Mechanisms Of Action, Yash Gupta, Steven Goicoechea, Jesus G. Romero, Raman Mathur, Thomas R. Caulfield, Daniel P. Becker, Ravi Durvasula, Prakasha Kempaiah

Journal of Food and Drug Analysis

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1,622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing …

Repurposing Lansoprazole And Posaconazole To Treat Leishmaniasis: Integration Of In Vitro Testing, Pharmacological Corroboration, And Mechanisms Of Action, Yash Gupta, Steven Goicoechea, Jesus G. Romero, Raman Mathur, Thomas R. Caulfield, Daniel P. Becker, Ravi Durvasula, Prakasha Kempaiah

Chemistry: Faculty Publications and Other Works

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing …

Bisindolylmaleimide Ix: A Novel Anti-Sars-Cov2 Agent Targeting Viral Main Protease 3clpro Demonstrated By Virtual Screening Pipeline And In-Vitro Validation Assays, Yash Gupta, Dawid Maciorowski, Samantha E. Zak, Krysten A. Jones, Rahul S. Kathayat, Saara-Anne Azizi, Raman Mathur, Catherine M. Pearce, David J. Ilc, Hamza Husein, Andrew S. Herbert, Ajay Bharti, Brijesh Rathi, Ravi Durvasula, Daniel P. Becker, Bryan C. Dickinson, John M. Dye, Prakasha Kempaiah

Chemistry: Faculty Publications and Other Works

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2′-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations & Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

A Network-Based Approach For Computational Drug Repurposing On Cancer Data, Ann Reba Thomas Alexander

Electronic Theses and Dissertations

In this thesis, we are interested in finding the best drugs that can be repurposed for the disease and able to find the adverse effects such drugs that are FDA-Approved. Developing an effective drug can be a time-consuming and expensive crucible method. Network-based machine learning methods are used for predicting a given drug for A that can be used for B. It aims at finding new indications for already existing drugs and therefore increases the available therapeutic choices at a fraction of the cost of new drug development. The perturbation gene expression data corresponding to the MCF7 cell line was …

Type I Topoisomerases As Potential Targets For Therapeutics, Ahmed Seddek

FIU Electronic Theses and Dissertations

DNA topoisomerases are universal enzymes that control the topological features of DNA in all forms of life. This study aims to find potential inhibitors of some of the DNA topoisomerases in bacteria and humans that can be developed into potential therapeutics.

The first aim of this study is to find potential inhibitors of bacterial topoisomerase I that can be developed into antibiotics. There is an urgent need to develop novel antibiotics to overcome the world-wide health crisis of antimicrobial resistance. Virtual screening and biochemical assays were combined to screen thousands of compounds for potential inhibitors of bacterial topoisomerase I. NSC76027 …

Profiling Of Fda-Approved And Clinical Trial Drugs Revealed Shared Cytotoxicity And Collateral Sensitivity In Resistant (H69ar) And Non-Resistant (H69) Small Cell Lung Cancer Cells. (Drug Repurposing In Cancer Chemotherapy), Pius Reyderg Agyemang

Electronic Theses and Dissertations

Some cancers are capable of “spitting out” drugs being fed to them, metaphorically speaking, becoming resistant to what were previously effective chemotherapeutics. In small-cell lung cancer (SCLC), an overexpression of a membrane protein (MRP1) and its transport activity can lead to chemotherapy failure. However, this study showed that certain drugs are selectively cytotoxic (exhibit collateral sensitivity) to MRP1-overexpressed SCLC (H69AR) cells. In this study, three drugs (Erlotinib, Pyrimethamine, Fludarabine) were identified to exhibit a dose-dependent collateral sensitivity on H69AR with IC50 values of ~3.5 μM, ~2 μM, and ~20 μM respectively. Halting the transport activity of the MRP1 with 25 …

Binary-Qsar Guided Virtual Screening Of Fda Approved Drugs And Compounds In Clinical Investigation Against Sars-Cov-2 Main Protease, Lalehan Oktay, Ece Erdemoğlu, İlayda Tolu, Yeşi̇m Yumak, Ayşenur Özcan, Eli̇f Acar, Şehri̇ban Büyükkiliç, Alpsu Olkan, Serdar Durdaği

Turkish Journal of Biology

With the emergence of the new SARS-CoV-2 virus, drug repurposing studies have gained substantial importance. Combined with the efficacy of recent improvements in ligand- and target-based virtual screening approaches, virtual screening has become faster and more productive than ever. In the current study, an FDA library of approved drugs and compounds under clinical investigation were screened for their antiviral activity using the antiviral therapeutic activity binary QSAR model of the MetaCore/MetaDrug platform. Among 6733-compound collection, we found 370 compounds with a normalized therapeutic activity value greater than a cutoff of 0.75. Only these selected compounds were used for molecular docking …

Antifungal Drug Repurposing, Jong H. Kim, Luisa W. Cheng, Kathleen L. Chan, Christina C. Tam, Noreen Mahoney, Mendel Friedman, Mikhail Martchenko Shilman, Kirkwood M. Land

College of the Pacific Faculty Articles

Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole …

Cytotoxic Analysis Of Old Drugs: New Drugs For Alzheimer’S Disease, Sebastian Yumiseba

Theses and Dissertations

Microglia are the resident immune cells of the CNS and constitute about 10% of all cells in the CNS. They have a vital role in Alzheimer’s pathogenesis as either cytotoxic or neuroprotective. Recent efforts are being put into repurposing drugs to target the microglia to treat Alzheimer’s disease.

Virtual Drug Repurposing Study Against Sars-Cov-2 Tmprss2 Target, Serdar Durdaği

Turkish Journal of Biology

Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC's NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in …

High Efficiency Drug Repurposing Design For New Antifungal Agents, Jong H. Kim, Kathleen L. Chan, Luisa W. Cheng, Lisa A. Tell, Barbara A. Byrne, Kristin Clothier, Kirkwood M. Land

College of the Pacific Faculty Articles

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated "chemosensitization" as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent …

High-Throughput Screen Of Drug Repurposing Library Identifies Inhibitors Of Sarcocystis Neurona Growth, Gregory D. Bowden, Kirkwood M. Land, Roberta M. O'Connor, Heather M. Fritz

College of the Pacific Faculty Articles

The apicomplexan parasite Sarcocystis neurona is the primary etiologic agent of equine protozoal myeloencephalitis (EPM), a serious neurologic disease of horses. Many horses in the U.S. are at risk of developing EPM; approximately 50% of all horses in the U.S. have been exposed to S. neurona and treatments for EPM are 60-70% effective. Advancement of treatment requires new technology to identify new drugs for EPM. To address this critical need, we developed, validated, and implemented a high-throughput screen to test 725 FDA-approved compounds from the NIH clinical collections library for anti-S. neurona activity. Our screen identified 18 compounds with confirmed …

High-Throughput Prediction And Analysis Of Drug-Protein Interactions In The Druggable Human Proteome, Chen Wang

Theses and Dissertations

Drugs exert their (therapeutic) effects via molecular-level interactions with proteins and other biomolecules. Computational prediction of drug-protein interactions plays a significant role in the effort to improve our current and limited knowledge of these interactions. The use of the putative drug-protein interactions could facilitate the discovery of novel applications of drugs, assist in cataloging their targets, and help to explain the details of medicinal efficacy and side-effects of drugs. We investigate current studies related to the computational prediction of drug-protein interactions and categorize them into protein structure-based and similarity-based methods. We evaluate three representative structure-based predictors and develop a Protein-Drug …