STRUCTURE-BASED VIRTUAL SCREENING STUDY OF FDA‑APPROVED DRUGS TO INHIBIT TP53 72 ARG/PRO VARIANT IDENTIFIED IN ACUTE LYMPHOCYTIC PATIENT VIA WHOLE EXOME SEQUENCING
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Keywords
TP53, Messense Mutation, Acute lymphocytic leukemia, Docking.
Abstract
Acute lymphoblastic leukaemia (ALL) is a significant threat to global health. Tumour suppressor gene TP53 mutations are often associated with a more aggressive form of leukaemia and poorer prognoses. This study conducted whole-exome sequencing of leukaemia patients at various treatment stages, including early diagnosis, relapse, and remission. We identified a missense 72 Arg/Pro (rs1042522) homozygous and heterozygous variant along with indel novel intron variant 376-158delAAAAAAA and 993+409delT in TP53. This mutational profile may serve as a predictor of poor treatment success in the Pakistani Pathan (Pakhtun) Population. Theoretical study explores the virtual repurposing of the FDA-approved drugs as inhibitors against these mutant TP53 cancers. The crystal structure of the TP53 proteins was downloaded from Alpha fold database and PDB and subjected to virtual screening by the DrugRep web server while using an FDA-approved drugs library as a ligands database. Our study revealed that Duvelisib and Robinin herb are the top-ranked inhibitors of MUT TP53 as compared to the reference chemotherapy. Duvelisib exhibited a docking score of −10.6 kcal/mol while Robinin herb scored –10.4 kcal/mol. In conclusion the two drugs deserve further consideration as possible cancer treatment option.
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Shahid Ullah
Department of Biochemistry Abdul Wali Khan University Mardan – 23200, KP, Pakistan
Alex Tonks
Department of Haematology, Division of Cancer & Genetics, School of Medicine Cardiff University United Kingdom
Abdulsalam M Alruwaili
Medical Laboratory Technology Department, College of Applied Medical Sciences, Northern Border University Arar 91431, Saudi Arabia
Hedib Alkoumi H Alrawili
Wolfson College, School of Medicine, Oxford University, England UK.
Asifullah Khan
Department of Biochemistry Abdul Wali Khan University Mardan – 23200, KP, Pakistan
Ahmad Salem Alanazi
King Fahad Specialist hospital, Dammam Saudi Arabia.
Amirah Sayah S Alkuwaykibi
Northern Borders Health Affairs Directorate, Infection Control Department, Arar 73311, Saudi Arabia
Carlos Eliel Maya-Ramírez
8Laboratorio de Diagnóstico molecular, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Carpio y Plan de Ayala S/N, Colonia, Casco de Santo Tomás, C.P.,11340 Ciudad de México, México.
Muhammad Arif Lodhi
Department of Biochemistry Abdul Wali Khan University Mardan – 23200, KP, Pakistan