ANALYZING THE EFFECT OF NSSNPS IN CYP1A1 TOWARDS BENZOTHIAZOLES BINDING

Objective: CYP1A1 involved in biotransformation of carcinogenic polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines/amides (HAAs) and results in electrophilic reactive intermediates that leads to toxicity and cancer, thus influencing the fields of cancer research.Benzothiazole and its analogs are known for their anti-tumor activity because they act as potent aryl hydrocarbon receptor (AhR) agonist thus binds AhR and results in induction of CYP1A1 which forms DNA adduct and leads to cell death by activation of apoptotic mechanism. The main aim of this study is to extrapolate the relationship between nsSNPs of CYP1A1 and their effects in Benzothiazoles binding capability.Methods: Computational analysis of deleterious mutations in CYP1A1 and their impact on its structure were as well as altered drug response to Benzothiazoles based drug DF 203, NSC 674495 were studied. Furthermore molecular dynamics simulation (MDS) approach was conducted to investigate conformational changes in the mutant protein structure with respect to its native conformation.Results: Our studies revealed that 6 deleterious nsSNPs CYP1A1 have the impact on structural stability based on secondary structural patterns and molecular dynamics and altered drug response was seen in nsSNP rs2229150 (R93W) for the drug 2-(4-amino-3-methylphenyl) benzothiazole (DF 203, NSC 674495).Conclusion: Our study would be helpful to understand the nsSNP effect on CYP1A1 which in turn leads to carcinogenesis as well as Benzothiazole (DF-203) binding affinity and designing individualized therapeutic treatments

EPITOPE PREDICTION AND STRUCTURAL ANALYSIS OF PRA ANTIGEN OF COCCIDIOIDES

Objective: Coccidioidomycosis is a life threatening human respiratory disease caused by Coccidioides immitis and C. posadasii. As the incidence of symptomatic Coccidioidomycosis increases worldwide, vaccine development strategy against Coccidioides is needed for both immunocompetent and immunocompromized individuals. An insight about PRA antigens in the pathogenesis of Coccidioidomycosis has the potential to develop a therapeutic intervention. Methods: In this study of ANN, SMM and QM based servers were used to predict promiscuous epitopes. Epitope structures were modeled using De novo based PEPFOLD server and minimized using Swiss model server. Further the modeled epitopes were tested for their binding affinity towards HLA alleles by means of peptide protein docking studies involving autodock. Results: A total of six antigenic epitopes ARISVSNIV, GRPTASTPA, ALNLFVEAL, LVAAGLASA, FSHALJALV, AEPTHEPTE of PRA showed hydrogen bonding with HLA alleles HLA-A*02:03, HLA B*27:05, HLA-A*02:01 with considerable bond distance. Thus, this systematic study on epitopes of Coccidioides study would be helpful in designing and developing novel PRA antigen based vaccine and inhibitor. Conclusion: These predicted sequences are potential vaccine candidates but functional/biological assays should be performed to verify whether they are indeed appropriate to be included in a vaccine formulation

DIFFERENTIAL EXPRESSION ANALYSIS OF KRUPPEL LIKE FACTORS 6 AND ANTAGONISTIC EFFECT STUDY OF CINNAMIC ACID - AN IN SILICO APPROACH

Objective: Krüppel-like factor 6 (KLF6) is the significant member of a DNA binding proteins which mainly involved in the transcriptional regulation as well various promising cellular processes such as cell proliferation and differentiation, cytokine signal-based inflammatory responses, and pluripotency activity of cells. Our computational studies involve KLF6 differential expression in breast cancer tissues based on web resources such as Oncomine and cBioportal. Methods: Oncomine and TCGA data-based CBioportal were the databases used to explore the KLF6 expression, and KLF6 was underexpressed in many of the breast cancer tissues than normal breast tissues. Major breast cancer datasets such as Curtis and TCGA supported the clinical-pathological role of KLF6, mutational frequencies. Further prognosis analysis was carried out using Survexpress and it revealed the survival rate and risk group categorization. Thus, KLF6 was considered as a therapeutic target and natural compound cinnamic acid antagonistic efficacy was analyzed based on molecular docking and simulation studies. Results: Systematic analysis of KLF6 gene expression in breast cancer would be helpful in exploring aspects of KLF6 as the potential drug target as well as prognostic disease marker identification. Molecular docking and dynamic study were carried out to evaluate the intermolecular interaction between the cinnamic acid and KLF6 and the docked complex stability after 5ns. Conclusion: Thus, the computational study demonstrated the cinnamic acid role as an anticancer compound to combat the overexpression of KLF6 to combat cancer. Further, in vitro and in vivo studies need to be carried out to know the insights of antagonistic effect