TY - JOUR
T1 - Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3β to Combat Alzheimer’s Disease
AU - Londhe, Saurabh G.
AU - Walhekar, Vinayak
AU - Shenoy, Mangala
AU - Kini, Suvarna G.
AU - Scotti, Marcus T.
AU - Scotti, Luciana
AU - Kumar, Dileep
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/8
Y1 - 2024/8
N2 - Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer’s disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer’s disease, capable of simultaneously inhibiting both GSK-3β and BuChE.
AB - Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer’s disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer’s disease, capable of simultaneously inhibiting both GSK-3β and BuChE.
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U2 - 10.3390/pharmaceutics16080991
DO - 10.3390/pharmaceutics16080991
M3 - Article
AN - SCOPUS:85202567620
SN - 1999-4923
VL - 16
JO - Pharmaceutics
JF - Pharmaceutics
IS - 8
M1 - 991
ER -