1. Farnesyl pyrophosphate synthase inhibitors with antiosteoporosis efficacy in ovariectomized rats: A mixed binding approach beyond bisphosphonates.
- Author
-
El-Sayed NF, El-Hussieny M, Mansour ST, Fouad MA, Saad MA, and Ewies EF
- Subjects
- Animals, Rats, Female, Humans, Structure-Activity Relationship, Molecular Docking Simulation, Diphosphonates pharmacology, Diphosphonates chemistry, Diphosphonates chemical synthesis, Molecular Structure, Rats, Sprague-Dawley, Dose-Response Relationship, Drug, Geranyltranstransferase antagonists & inhibitors, Geranyltranstransferase metabolism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors chemistry, Enzyme Inhibitors chemical synthesis, Ovariectomy, Osteoporosis drug therapy, Osteoporosis metabolism
- Abstract
The primary focus of bisphosphonate medications is on targeting human farnesyl pyrophosphate synthase (hFPPS), an essential regulator of mammalian isoprenoids. Yet, these drugs encounter limitations due to their restricted "druglike" properties and their effectiveness primarily in treating skeletal disorders. In this study, we synthesized novel non-bisphosphonate compounds, using 4,4'-(ethane-1,2-diylbis(oxy))bis(3-methoxybenzaldehyde) (1) as a starting compound, with the aim of targeting hFPPS through a mixed binding approach. Among the various compounds tested, compounds 4a and 4b exhibited significant inhibition of hFPPS activity, with IC
50 values of 1.108 and 1.24 μM, respectively. Docking studies further revealed that both compounds bound within the allylic binding site and near the isopentenyl diphosphate (IPP) site within the hFPPS pocket. Molecular dynamic simulations were performed on the best docking pose of the most potent compound 4a to confirm the formation of a stable complex with hFPPS. In an in vivo study conducted on ovariectomized rats, various biochemical markers including osteocalcin, estradiol, osteoprotegerin, bone mineral content, and density were negatively impacted, while levels of bone specific alkaline phosphatase, receptor activator of nuclear factor kappa-Β ligand, serum/urinary calcium, and phosphate increased. Notably, compound 4a exhibited antiresorptive properties similar to zoledronate, effectively restoring most of the perturbed biochemical estimations. These findings suggest the potential of compound 4a, a non-bisphosphonate compound, as alternative therapeutic agents for combating osteoporosis., Competing Interests: Declaration of competing interest We confirm that this work is original, was not published elsewhere, and is not currently under consideration for publication. We have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)- Published
- 2024
- Full Text
- View/download PDF