Rational in silico drug design based on natural compounds to targeting DNA and DNA polymerase alongside with their complex

As it is widely known, the correct transmission of chromosomes is valuable for the inheritance, which is facilitated by the DNA replication process .The life cycles of cells are not flawless, and a variety of environmental agent alongside with reactive metabolites that are generated during the life cycle of cells can cause lesions in DNA structures [1].On the other hand, neoplastic transformation and genome instability, which are the results of replication stress, can be another reason for DNA damages [2].At first glance, we expect cells to employ pathways to repair DNA damages. Under replication stress, the cells are supposed to replicate damaged DNA before the mitosis phase of cells' life cycles. Undoubtedly, the copies this damaged DNA will pass down to both daughter cells, and this mechanism, which is called DNA damage tolerance, will be repeated for daughter cells over and over and result in cancerous cells [3].Many proteins involved in the production of these cancerous cells, including DNA polymerase η, can be the targets of the new designed anticancer drugs .DNA polymerases are participating in crucial steps of DNADNA replications in that that they involve in functioning in the replication of the genomic material, playing arole in DNA repair, and taking part in aprocess called translesion DNA synthesis (TLS) [4].Fifteen mammalian DNA polymerases have been identified, but our focus in this this study is DNA polymerase η (Polη ). Polymerase η among the other members of its family unique enzyme; for instance, it bypasses the barriers caused dominant UV lesion [5].According to many studies, high levels of expressions of polymerase η have been associated with low rates of patients' survivals [6].Even in cases such as acute myeloid leukaemia, the polymerase η can be a good target for the design of new anticancer drugs .Many attempts have been made to discover the pathway in which the polymerase η is involved. For example, this enzyme can perform translesion DNA synthesis, even in the presence of cisplatin adducts [7].Cytarabine, as the rapeutic drug, is used to treat acute myeloid leukaemia and is expected to inhibit DNA polymerase η. However, recently, it was found that this this drug could form covalent bonds with DNA by the aim of DNA polymerase η.Thus, DNA polymerase η (Pol η )cancan continue DNA synthesis from Cytarabine terminated primers, which leads to the drug resistance and DNA mutation. Cytarabine, as the synthetic analogue of deoxycytidine, enters the cell in different ways .It can be transported across the cell membrane by a nucleoside carrier system [8].Diffusion at high concentration of this drug has been reported too [9].Many adverse effects of Cytarabine including myelosuppression [10 ], Anaphylactic reactions [11 ], Drug Fever [12 ], a very painful erythematous palmar-plantar bulla formation [13 ], Subacute pulmonary failure [14 ], and gastrointestinal toxicity [15 ]stimulated our research group to find the natural -based drug that can be used instead of Cytarabine.