Study of ligand-based virtual screening tools in computer-aided drug design

Virtual screening is a central technique in drug discovery today. Millions of molecules can be tested in silico with the aim to only select the most promising and test them experimentally. The topic of this thesis is ligand-based virtual screening tools which take existing active molecules as starting point for finding new drug candidates. One goal of this thesis was to build a model that gives the probability that two molecules are biologically similar as function of one or more chemical similarity scores. Another important goal was to evaluate how well different ligand-based virtual screening tools are able to distinguish active molecules from inactives. One more criterion set for the virtual screening tools was their applicability in scaffold-hopping, i.e. finding new active chemotypes. In the first part of the work, a link was defined between the abstract chemical similarity score given by a screening tool and the probability that the two molecules are biologically similar. These results help to decide objectively which virtual screening hits to test experimentally. The work also resulted in a new type of data fusion method when using two or more tools. In the second part, five ligand-based virtual screening tools were evaluated and their performance was found to be generally poor. Three reasons for this were proposed: false negatives in the benchmark sets, active molecules that do not share the binding mode, and activity cliffs. In the third part of the study, a novel visualization and quantification method is presented for evaluation of the scaffold-hopping ability of virtual screening tools.

Identification of Epigenetic Targets in Prostate Cancer for Therapeutic Development

Recurrent castration resistant prostate cancer remains a challenge for cancer therapies and novel treatment options in addition to current anti-androgen and mitosis inhibitors are needed. Aberrations in epigenetic enzymes and chromatin binding proteins have been linked to prostate cancer and they may form a novel class of drug targets in the future. In this thesis we systematically evaluated the epigenenome as a prostate cancer drug target. We functionally silenced 615 known and putative epigenetically active protein coding genes in prostate cancer cell lines using high throughput RNAi screening and evaluated the effects on cell proliferation, androgen receptor (AR) expression and histone patterns. Histone deacetylases (HDACs) were found to regulate AR expression. Furthermore, HDAC inhibitors reduced AR signaling and inhibited synergistically with androgen deprivation prostate cancer cell proliferation. In particular, TMPRSS2- EGR fusion gene positive prostate cancer cell lines were sensitive to combined HDAC and AR inhibition, which may partly be related to the dependency of a fusion gene induced epigenetic pathway. Histone demethylases (HDMs) were identified to regulate prostate cancer cell line proliferation. We discovered a novel histone JmjC-domain histone demethylase PHF8 to be highly expressed in high grade prostate cancers and mediate cell proliferation, migration and invasion in in vitro models. Additionally, we explored novel HDM inhibitor chemical structures using virtual screening methods. The structures best fitting to the active pocket of KDM4A were tested for enzyme inhibition and prostate cancer cell proliferation activity in vitro. In conclusion, our results show that prostate cancer may efficiently be targeted with combined AR and HDAC inhibition which is also currently being tested in clinical trials. HDMs were identified as another feasible novel drug target class. Future studies in representative animal models and development of specific inhibitors may reveal HDMs full potential in prostate cancer therapy

Co-creating Value For Smart Phone Operating Systems Via Virtual Discussion Forums

In the traditional way, value is created by manufacturer or producer of a product without engaging the customers. So, traditionally value creation is a monopoly in the part of a manufacturer. After gathering all the raw materials the manufacturers are inserting value to a product. And the inserted value is recognized in the time of consuming the product. In the modern time though there is traditional way of value creation but with the increase of more educated, smart, and technically sound customers the idea of value creation has changed. Now, customers are also contributing in value creation as value co-creator even before the product is consumed. This scenario has been encountered in the thesis with the main purpose of how value is cocreated in smart phone operating systems. The purpose is further divided into the following supobjectives: o What is value co-creation in smart phone operating systems? o Who participates in value co-creation in smart phone operating systems? o What are the procedures that are involved in value co-creation in smart phone operating systems? The research was conducted as a qualitative desk study by observing two of the leading smart phone operating system providers. Data has been collected from the official discussion forum of both the operating system providers. Other general concepts relating to the purpose of the study has been encountered through literature review. The research findings reveal that customers and companies both together co-create value of anticipated level when they communicate and interact with each other. However, most of the time customer to customer interactions, dialogues and discussions that come out in the core conversation help the value co-creation. The value co-creation framework sets up the customer at the main focus of value creation theory. By nullifying the inherited notion that companies only create value within its boundary and provide it to their customers in exchange of currencies. Rationally, it has been commenced that the firms are merely compromising value propositions to its customers. But the value has been co-created in a point where offerings are combined and interacted with customers’ capabilities, knowledge, resources and perceptions. This new perspective has radically altered the prospect of firms towards its customers. Typically customers are now taking part in value cocreation as a crucial member.