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All living cells have a tendency to maintain their genomic stability with as few mutations as possible. This is of crucial importance to the normal function of cells in complex environments, correctly timed cell cycle progression, and a commitment to apoptosis when appropriate (Wood, et al., 2001). In this context, the balance between constancy and mutability in the context of genomic stability must be precisely regulated and controlled. To achieve this objective, a number of multiple and overlapping DNA repair pathways have been crafted within the cell (Harper & Elledge, 2007). Nevertheless, an elevated activity of these pathways could significantly decrease cancer cells’ sensitivity to many known anticancer agents and, consequently, increase their antitumor drug resistance. This unforeseen role stems from the fact that most cancer chemotherapy in clinical use today, directly or indirectly damage DNA by causing singleor double-stranded DNA breaks or by interfering with the functions of crucial DNA interacting proteins. As a natural cellular response, following the detection of damage, DNA repair pathways attempt to restore the genome and restore the normal state of the cell. During this course, the cell’s fate is mainly determined by the effectiveness of DNA repair mechanisms which allow the cell to survive or, if the damage is too heavy, induce apoptosis, causing the cell to die (Harper & Elledge, 2007). Consequently, to improve existing cancer therapies, DNA repair pathways have been considered as novel therapeutic targets. Several DNA repair inhibitors have been reported, some of which have been recently proven to be successful (Damia & D'Incalci, 2007) This review paper focuses on our efforts directed at in silico searches for inhibitors of proteins that control the DNA repair circuitry. The targets chosen here play critical roles in tumor cell initiation and progression, hence their regulation offers promise for the improvement of current cancer therapy. Two of these targets are DNA repair proteins that are directly linked to the hallmark “relapse” or “drug resistance” phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1) (Kang, et al., 2006), and DNA polymerase beta (pol β) (Parsons, et al., 2004). The former is a key player in Nucleotide Excision Repair (NER), while the latter is the error-prone polymerase of Base Excision Repair (BER). The third target is p53 (Teodoro, et al., 2007), a so-called guardian protein of the genome that is inactivated in more than half of all human cancers investigated. An additional aim of this review is to share with the reader our experience as a computational drug discovery group by describing the virtual screening protocol we have developed in order to successfully address these biological problems. This chapter is divided into two main sections. The first gives a description of the computational workflow that we typically

Virtual Screening for DNA Repair Inhibitors