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Mohammed Al-Seragi

Abstract

Introduction: Lead is a naturally occurring toxin which is prone to bioaccumulation in the human skeleton. Problematically, conventional chelating agents fail to acutely uptake lead – inadvertently targeting important divalent metal cations in the body (e.g., zinc) while primarily addressing only the plasma-bound toxins. For these reasons, this report aims to model a novel bisphosphonate-ligand conjugate (NBLC) which A. bears remarkable specificity for the bone, B. reduces bone-lead turnover into the blood via suppression of osteoclast activity mediated by Farnesyl Pyrophosphate Synthase (FPPS), and C. favorably complexes with lead amongst all other minerals in the body while depositing calcium in place of the uptaken metal.


Methods: The NBLC molecular model was designed on Marvinsketch and optimized in three-dimensional space for ligand-receptor docking using UCSF Chimera. The NBLC and other conventional bisphosphonates (Zoledronate and NE10575) were uploaded to Webina 1.0.4 to determine an average free energy (ΔG) and, subsequently, an average drug binding affinity (Kd) of the three most energetically stable FPPS-molecule complexes to gauge efficacy of the moieties as allosteric inhibitors. Thereafter, the average bond length of four coordinate covalent bonds between the bisphosphonates (including the NBLC) and two hydroxyapatite crystals was determined as a measure of molecular binding affinity to the bone.


Results: The NBLC achieved a Kd of 0.062±0.003. By One-Way ANOVA, this result was statistically lower than the results obtained by the other FPPS-bisphosphonate complexes (p=2.59×10-5), reinforcing that the NBLC is a more potent allosteric inhibitor of the osteoclast-mediating enzyme. Additionally, the average coordination bond length of the NBLC-hydroxyapatite complex was 3.13±0.7Å, which, as determined via a two-tailed T-test, bore a statistically insignificant difference with the results obtained using Zoledronate (p=0.991).


Discussion: The results demonstrate that the NBLC is capable of binding bone hydroxyapatite and allosterically inhibiting FPPS.


Conclusion: The collected data suggests that the NBLC successfully meets the first two criteria defined in the introduction. As per the final criterion, this paper paves way for future work in synthesis and characterization of the NBLC to experimentally determine the thermodynamic stability of its metal complexes and ascertain its ability to selectively uptake lead while depositing calcium.

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Section
Primary Research