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Exploring the composition of protein-ligand binding sites for cancerous inhibitor of PP2A (CIP2A) by inhibitor guided binding analysis: paving a new way for the Discovery of drug candidates against triple negative breast cancer (TNBC).
Ibitoye, Oluwayimika; Ibrahim, Mahmoud A A; Soliman, Mahmoud E S.
Afiliación
  • Ibitoye O; Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
  • Ibrahim MAA; Center for Bioinformatics and Drug Design, Adekunle Ajasin University, Akungba-Akoko, Nigeria.
  • Soliman MES; Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
J Recept Signal Transduct Res ; 43(6): 133-143, 2023 Dec.
Article en En | MEDLINE | ID: mdl-38166612
ABSTRACT
Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis in vivo. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted in silico site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with ΔG critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: J Recept Signal Transduct Res Asunto de la revista: BIOQUIMICA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Sudáfrica

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias de la Mama Triple Negativas Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: J Recept Signal Transduct Res Asunto de la revista: BIOQUIMICA / FISIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: Sudáfrica