AbstractsBiology & Animal Science

Transporter proteins and receptors play a pivotal role in drug absorption, distribution and excretion. However, very few of the transporters have been crystallized and not all pharmaceutically significant receptors have been studied extensively. Nonetheless, currently available functional as well as structural data provide an attractive scaffold for generating combined models that merge ligand-based structure-activity relationship and protein-based homology structures. The resultant models offer features that extend the predictive function of previous single models. This dissertation is aimed at presenting alternative approaches for studying transporter and receptor structure by applying in silico technologies with the following specific aims: (1) to develop thoroughly validated, highly predictive Quantitative Structure Activity Relationship (QSAR) models and pharmacophore models for pharmaceutically important transporters and receptors; (2) to generate comparative three-dimensional models for essential drug targets; and (3) to identify novel inhibitors towards significant drug targets through database screening using pharmacophore models generated in aim 1. Chapter 1 presents an overview of in silico approaches for studying drug targets. A summary of the significance of transporters and receptors in human health is provided along with a comprehensive review of recent successful in silico applications. Also included is a detailed description of the methods used in later studies. Chapter 2 – 9 describe the QSAR and pharmacophore studies as well as pharmacophore-based database screening results for transporters involved in: drug absorption, i.e., nucleoside transporter and peptide transporters; drug elimination, i.e., organic cation transporter, organic anion transporting polypeptides and drug efflux, i.e., P-glycoprotein, and for pharmaceutically important receptors, i.e., androgen receptor, bile acid receptor. The significance of each drug target is first presented, followed by the description of the modeling study. The implication of each model is discussed after the validation process. The database screening results are also listed with experimental verification, when available. Chapter 10 will summarize previous studies and compare advantages and disadvantages of different in silico methods. It will also discuss future directions of in silico modeling studies based on the work outlined in this dissertation.