Center for Structural Biology, Department of Biochemistry (David Rodgers)
Acetylcholine is a neurotransmitter that is involved in a number of neurologic functions. Certain neurological-associated diseases (e.g. congenital neuromuscular disease and Alzheimer disease) may be due, in part, to alterations in certain cholinergic neurons. The synthesis of acetylcholine from acetyl-CoA and choline within the terminal end of the nerve is
ChAT have been identified in patients with inherited disorders affecting the neuromuscular junction (congenital myasthenic syndromes).
This research involved the identification of potential binding sites for ligands on this enzyme and the computational de novo synthesis of candidate drugs capable of reversing the effect of these mutations in vivo.

Results:

• Determined the 3-dimensional solvated structure of ChAT

• Identified a number of key internal and surface ligand-binding sites on ChAT.

• Completed de novo synthesis of pharmacophores corresponding to each of the identifed key ligand-binding sites.

• Identified a candidate drug consistent with the pharmacophore structure at one of the key ligand-binding sites employing virtual molecular docking analysis.

Neprilysin (enkphalinase) is a zinc-dependent metallo-endopeptidase that is widely expressed in mammalian tissues, including neural synapses in the central nervous system. This enzyme cleaves a number of physiological substrates. As a consequence, it has been suggested that modulation of this enzyme’s specificity toward specific substrates might enhance its use as a potentiall therapeutic agent for the treatment of certain neurological diseases such as Alzheimer’s disease. It also has activity associated with other systemic processes. Inhibition of neprilysin acitivity may also provide a mechanism for treatment of pain and hypertension.

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure following its conversion from angiotensin I to angiotensin II and is a target for the treatment of antihypertension. One suggested approach for the treatment of congestive heart failure and chronic hypertension inhibition of the formation of angiotensin II by endopeptidase cleavage.

• Investigation of the binding of angiotensin to neprilysin by virtual molecular docking analysis.

Current work in progress:

Atom typing of a tetrahedral zinc (Zn) atom bonded to four specific amino acid residues. Although the atom type for this particular Zn atom is required to run molecular dynamics simulations of certain Zn-containing proteins, no atom type for this specific Zn atom currently exists. This data will initially be used to run MD simulations of neprilysin complexed with angiotensin to investigate the binding of angiotensin by neprilysin. The atom type data will also be made available for the entire computational biology research community.

Students

Software

Publications

2014

Fang, L.;Chow, K.M.;Hou, S.;Xue, L.;Chen, X.;Rodgers, D.W.;Zheng, F.;Zhan, C.G. "Rational design, preparation, and characterization of a therapeutic enzyme mutant with improved stability and function for cocaine detoxification." ACS chemical biology 9, 8 (2014): 1764-72. PubMed Link | Full text

Grants

Rodgers, David NO ID KY EPSCoR: Powering the Kentucky Bioeconomy for a Sustainable Future (Rodgers Scope) KY Council on Postsecondary Education 6/1/2014 - 5/31/2015 SCOPE
Rodgers, David 1P30GM110787-01 COBRE for the Center for Molecular Medicine - Protein Core National Institute of General Medical Sciences 7/1/2014 - 4/30/2019 SCOPE
Rodgers, David 5R03NS079818-02 Cavities in Choline Acetyltransferase and Neuromuscular Disorders National Institute of Neurological Disorders & Stroke 7/1/2012 - 6/30/2015 $145,901
Rodgers, David 5P20GM103486-10 Center of Biomedical Research Excellence in the Molecular Basis of Human Disease - PROTEIN ANALYTICAL CORE National Institute of General Medical Sciences 9/1/2004 - 6/30/2014 SCOPE