A comprehensive computational approach for the identification of structure-based potential pharmacological candidates as selective AKR1B1 and AKR1B10 inhibitors: repurposing of purine alkaloids for the treatment of cancer
2023 (English)In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 41, no 16, p. 7892-7912Article in journal (Refereed) Published
Abstract [en]
Significant metabolic pathways have been linked to AKR1B1 and AKR1B10. These enzymes are crucial biological targets in the therapy of colon cancer. In the past several decades, drug repurposing has gained appeal as a time and cost-efficient strategy for providing new indications for existing drugs. The structural properties of the plant-based alkaloidal drugs theobromine and theophylline were examined using density functional theory (DFT) computations, where the B3LYP/SVP method was used to quantify the dipole moment, polarizability, and optimization energy. Optimized structures obtained through DFT studies were docked inside the active pocket of target proteins to evaluate their inhibitory potential. Moreover, molecular dynamic simulation provides significant insight into a dynamic view of molecular interactions. The findings of current revealed theobromine and theophylline as strong AKR1B1 and AKR1B10 inhibitors, respectively. In addition, the anti-cancer potential of theophylline and theobromine was validated by targeting various tumor proteins, i.e. NF-kappa B, cellular tumor antigen P53 and caspase-3 using a molecular docking approach. Theobromine was found to be strongly interacted with NF-kappa B and caspase-3, whereas theophylline potentially inhibited cellular tumor antigen P53. In addition, the ADMET characteristics of theobromine and theophylline were identified, confirming their drug-like capabilities. These results should open the way for further experimental validation and structure-based drug design/repurposing of AKR1B1/AKR1B10 inhibitors for the treatment of colon cancer and associated malignancies. Communicated by Ramaswamy H. Sarma
Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC , 2023. Vol. 41, no 16, p. 7892-7912
Keywords [en]
Aldo-keto reductase; molecular docking; molecular dynamic simulations; ADMET
National Category
Biophysics
Identifiers
URN: urn:nbn:se:liu:diva-189489DOI: 10.1080/07391102.2022.2127906ISI: 000865698100001PubMedID: 36214620OAI: oai:DiVA.org:liu-189489DiVA, id: diva2:1706180
Note
Funding Agencies|Princess Nourah Bint Abdulrahman University Researchers Supporting Project, Riyadh, Saudi Arabia [PNURSP2022R12]
2022-10-252022-10-252023-11-16Bibliographically approved