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Downloads/Drugs/Guidancecomplianceregulatoryinformation/ Guidances/Ucm292362.Pdf (Accessed on 4 March 2014) Kent Academic Repository Full text document (pdf) Citation for published version Mohsen, Sharifi (2014) Computational Estimation of Biliary Excretion of Compounds and the Role of Transporters. Doctor of Philosophy (PhD) thesis, University of Kent. DOI Link to record in KAR https://kar.kent.ac.uk/84748/ Document Version UNSPECIFIED Copyright & reuse Content in the Kent Academic Repository is made available for research purposes. Unless otherwise stated all content is protected by copyright and in the absence of an open licence (eg Creative Commons), permissions for further reuse of content should be sought from the publisher, author or other copyright holder. Versions of research The version in the Kent Academic Repository may differ from the final published version. Users are advised to check http://kar.kent.ac.uk for the status of the paper. Users should always cite the published version of record. Enquiries For any further enquiries regarding the licence status of this document, please contact: [email protected] If you believe this document infringes copyright then please contact the KAR admin team with the take-down information provided at http://kar.kent.ac.uk/contact.html Computational Estimation of Biliary Excretion of Compounds and the Role of Transporters Thesis By Mohsen Sharifi In Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy University of Kent © 2014 All Rights Reserved 1 Acknowledgements I would like to express the deepest appreciation to my principal supervisor, who was so patient with me. Dr Tara Ghafourian, who embodied the figure of a kind mentor, provided support and instilled mental stimulation in regards to my research. I would never have been able to finish my dissertation without her guidance. Dr Ghafourian inspirerd me to take pride in my research. She patiently corrected my writing, her enthusiasm for research efforts will have a significant effect on my future projects. Providing support letters, she helps me to win a number of student bursaries to attend different conferences and workshops. Without her persistence, I would have lost my motivation. Dr Ghafourian gave direction when it was most needed. Her valuable advice throughout this process kept me focused on my research topic. I say a big THANK YOU! Special thanks goes to my second supervisor, Dr Ali Nokhodchi for his brilliant suggestions and supports. I would like to express my special appreciation and thanks to Prof. Iain Cumming for all his helps and supports. Also I would like to thank the administration group of Medway School of Pharmacy, especially Richard Hammersley and Tom Bore for their excellent guidance. I also thank the wonderful staff in the Chemistry Department as well as in other departments for always being so helpful and friendly, particularly, Dr Vadim Sumbayev and Dr Maxwell Casely-Hayford who are genuinely nice and want to help out and I’m glad to have interacted with them. If I have forgotten anyone apologize. Also, I am grateful to my close friends, Mehrdad Mirzaee, Ehab Al-Moubarak and Rafał Wyszyński, who helped me tremendously. Thank you guys, you always listened to my complaints and made my boring and hard life in Medway easier. Also, worthy of appreciation is to Danielle Newby for her assistance, apart from being a reliable friend, she always willing to help and gives her best suggestions. Danielle corrects my English and teaches me some interesting English idiomatic expressions such as “give someone a wedgie” and “going to getting smashed”. 2 Besides, I heartily thankful to Prof. Martin Michaelis at School of Biosciences, Kent University for giving me the opportunity to participate in collaborative projects on anticancer drugs. I gladly express my gratitude to University security staffs at the Medway’s Gate House, they are really helpful and let me work till very late and on all Saturdays and Sundays. Lastly, I would like to thank my family for all their love and encouragement, especially my dad, Dr Sharifi, who fully supported me financially for my PhD and also, always guided me in my life. Also, I would like to thank my mom who support me morally and prayed for me. Without them I wouldn’t be where I am today. 3 Table of Contents Acknowledgements………………………………………………………….…...…2 Table of Contents…………………………………………………………… ……..4 List of Tables………………………………………………………………… ……9 List of Figures………………………………………………………………… ….11 Abstract………………………………………………………………………… ...15 1. Introduction…………………………………………………………………… .16 1.1. Drug Discovery and Development ................................................................ 16 1.2. Pharmacokinetics ........................................................................................... 19 1.3. Elimination of Drugs ..................................................................................... 21 1.3.1. Renal Excretion....................................................................................... 23 1.3.2. Elimination by the Liver ......................................................................... 24 1.3.3. Elimination by the Other Sites ................................................................ 26 1.4. Function of the Liver and its Role in Drug Elimination ................................ 27 1.4.1. Biliary Excretion of Drugs ...................................................................... 28 1.4.2. Metabolism of Drugs .............................................................................. 31 1.5. Elimination by Membrane Transporters ........................................................ 33 1.5.1. Peptide Transporters (PEPT) .................................................................. 35 1.5.2. Organic Anion-Transporting Polypeptides (OATP) ............................... 36 1.5.3. Organic Ion Transporters (OAT, OCTN and OCT) ............................... 38 1.5.4. H+/ Organic Cation Antiporter (MATE) ................................................ 41 1.5.5. ABC Transporters ................................................................................... 42 1.5.5.1. ABC Transporters in Multidrug Resistance ..................................... 44 1.5.5.1.1. P-glycoprotein (ABCB1 Subfamily, MDR) .............................. 46 1.5.5.1.2. Multidrug Resistance-Associated Protein (MRP, ABCC Subfamily) ................................................................................................. 50 4 1.5.5.1.3. Breast Cancer Resistance Protein (BCRP, ABCG2 Subfamily)53 1.6. Assessment of drug-transporter Interactions ................................................. 53 1.7. In silico Methods in Drug Discovery ............................................................ 57 1.7.1. Quantitative structure-activity Relationships (QSAR) ........................... 58 1.7.1.1. Molecular Descriptors ...................................................................... 58 1.7.1.1.1. 2D Molecular Descriptors ......................................................... 60 1.7.1.1.2. 3D Molecular Descriptors ......................................................... 61 1.7.1.2. QSAR Model Development and Validation .................................... 62 1.7.1.2.1. Statistical Modeling Techniques ............................................... 63 1.7.1.2.2. Validation of QSAR Models ..................................................... 65 1.7.1.2.2.1. Applicability Domain ......................................................... 67 1.7.2. Enzyme-ligand Docking ......................................................................... 69 1.7.2.1. Conceptual Frame and Methodology of Molecular Docking .......... 69 1.7.2.2. Scoring Functions ............................................................................ 71 2. Aims and Objectives…………………………………………………………….73 3. Methods…………………………………………………………………………76 3.1. Datasets ......................................................................................................... 76 3.2. Calculation of Molecular Descriptors ........................................................... 76 3.2.1. ACD Labs/LogD Suite 12.0.................................................................... 76 3.2.2. TSAR 3D ................................................................................................ 78 3.2.3. Molecular Operating Environment (MOE)............................................. 79 3.2.4. Symyx QSAR version 2.2 ....................................................................... 79 3.3. Development and Validation of QSAR Models ............................................ 80 3.3.1. Stepwise Regression Analysis ................................................................ 81 3.3.2. Classification and Regression Trees (C&RT) ........................................ 82 3.3.3. Interactive Tree (I-tree) Using C&RT .................................................... 83 3.3.4. Chi-square Automatic Interaction Detector (CHAID)............................ 83 5 3.3.5. Boosted Trees (BT) ................................................................................. 84 3.3.6. Random Forest Trees Model (RF) .......................................................... 84 3.3.7. Multivariate Adaptive Regression Splines (MARS) Model ................... 85 4. QSAR Models for Biliary Excretion……………………………………………87 4.1. Introduction ................................................................................................... 87 4.2. Methods ......................................................................................................... 90 4.2.1. The Dataset
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