Computational simulation guided prediction of the inhibitory effect of curcumin, diallyl sulfide and its conjugates on ALDH1A1 to target breast cancer stem cells (BCSCs)

. Despite the significant advancements in clinical and laboratory research, breast cancer remains a formidable challenge due to its high incidence, recurrence and mortality rate. The emerging paradigm emphasizes the pivotal role of cancer stem cells in compelling cancer initiation and recurrence attributed to the resistance against conventional radio and chemotherapy, thereby leading to poor prognosis and disease relapse post-treatment. Aldehyde dehydrogenase (ALDH1A1) is the putative stemness biomarker in breast cancer stem cells. It has been attributed to drug resistance in chemotherapy, especially against the drugs derived from aldehydic intermediate in action mechanism, cell differentiation and oxidative stress response. Since time immemorial, natural products have been employed in traditional medicine systems for their therapeutic and chemopreventive properties. Curcumin, an active polyphenol present in turmeric, plays a significant role in impeding the growth of BCSCs. However, the clinical efficacy of curcumin is restrained due to its poor bioavailability, limited absorption, rapid metabolism, and systemic elimination. To address this challenge, efforts have been directed towards synthesizing curcumin conjugates with diallyl sulfide to enhance its bioavailability. Computational tools such as molecular docking, molecular dynamics simulations and end-state MMGBSA binding free-energy calculations were employed to predict the optimal binding of curcumin conjugates with ALDH1A1 and provide valuable insights into their potential binding affinity and therapeutic efficacy. The enhanced bioavailability of curcumin may be attributed to the enhanced therapeutic activity against the BCSCs. Furthermore, synthesizing curcumin conjugates holds promise in cancer Chemoprevention. .