PDE4D-targeted Small Molecules from Computational Screening for Dementia
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Sophie Ma
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Phosphodiesterase 4D enzymes hydrolyze cyclic adenosine monophosphate (cAMP), a messenger molecule that signals neurons and the release of neurotransmitters, which are crucial to the development of memory and cognition. Inhibiting PDE4D offers promising drug treatments for neurological diseases, including dementia and other illnesses associated with memory, disorders that impair mental abilities, limit daily functioning, and complicate the lives of those affected. The goal of this study was to determine binding sites on the PDE4D protein using geometric and energetic methods and identify promising locations for binding. The PDE4D enzyme was virtually screened for interactions between the protein and the compound, revealing fitting compounds for these interactions. The docking of compounds onto the protein and their energetic interactions were quantified, providing further details on each interaction and its strength. To ensure the compounds would be absorbed and excreted properly, each molecule was analyzed according to ADME drug guidelines to become candidates for drug treatment. The toxicity levels of the compounds raise risks to the human body; by ensuring that the toxicity was harmless, 1 lead compound was successfully discovered for potential treatment, along with 2 backup compounds that met all other criteria in all experiments. These criteria included low drug and RMSD scores in the pharmacophore maps, negative ∆G values in docking of the molecules, 0 violations of Lipinski’s rule and guidelines of ADME, and a high LD50. These compounds would inhibit the catalysis of cAMP, improving cognitive symptoms of dementia and associated disorders.
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Sophie Ma
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