Identification of Therapeutic Targets of Kaposi Sarcoma and Effectivity of Available Therapeutics

Abstract

Kaposi Sarcoma is a malignancy of antiproliferative origin. Its etiology is linked to Kaposi Sarcoma-associated Herpes Virus or Human Herpes Virus 8 abbreviated as HHV8. The causative agent of Kaposi sarcoma is HHV8 consists of double-stranded DNA enclosed in an icosahedral capsid that remains in a latent state and switches to the lytic stage at any point in life with humans being natural hosts to HHV8 and is capable of modulating human immune and signaling pathways. Kaposi sarcoma lesions incorporate mucosal regions and skin that are featured with macules, nodules, and papules of purple, brown, or red color. There are 4 variants of Kaposi Sarcoma based on epidemiology and prognosis of the disease which include classic, endemic, iatrogenic, and epidemic types. This research primarily focuses on the identification of genes involved in the prognosis of Kaposi sarcoma with the help of high throughput sequencing platform and microarray analysis. Therefore, the genes involved at the onset and progression of Kaposi sarcoma are identified. Moreover, differentially expressed genes are identified with the comparison of various datasets and signaling pathways modulated as a result of the disease are determined. Moreover, variety of ligands are docked to the shortlisted therapeutic target to hand-pick the most effective ligand against Kaposi sarcoma. The short-listed differentially expressed genes included CA6, MIA, DCD, STRIP1, WNT4, FXDY1, IKBKE, and EXTL2, AQR, TIE2 and RBP2. These are the differentially expressed genes that were identified as a result of the analysis involved in the oncogenesis. Therefore, the protein Glutathione Transferase Protein 1 abbreviated as GSTP1 is reported to have a major role in the progression of Kaposi sarcoma that hides tumor cells from apoptosis by inhibiting of MAPK pathway by protein-protein interaction. Therefore, the mechanism of action of GSTP1 in inhibition of MAPK pathway is the interaction of GSTP1 with c JUN that delivers anti apoptotic signals that lead to apoptosis inhibition. The inhibition of apoptosis is a key component in carcinogenesis. This pathway is inhibited 1 Abstract in Kaposi sarcoma which inhibits apoptosis and leads to the survival of cancer cells. The second focus of this thesis was virtual screening of ligands to the target protein that was GSTP1.A variety of ligands that incorporated inhibitors of GSTP, anti-cancer drugs and drugs of Kaposi sarcoma were docked to GSTP1. A range of binding affinities were observed between the ligands and the protein that ranged from -4 Kcal/- mol to -10 Kcal/mol . As a result, the top 10 ligands with the maximum binding affinities were BDBM50458517, BDBM50562983, DB06595, DB11942, DB11986, DB12483, DB12887, DB14568 and DB15035. The docking between protein and ligand revealed BDBM50458517 to have a significant role in the treatment of Kaposi sarcoma that was previously just employed as an anti-cancer drug by promoting apoptosis. This analysis was based on international data. In this case we need data at the national level so that the differentially expressed genes from the Pakistani population can be identified and compared with the genes of the international population. 2