Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation


Arts and Sciences



First Advisor

Chang-Guo Zhan

Second Advisor

Chris Richards


Computational chemistry methods have been greatly used and has great potential in drug discovery and understanding the detailed molecular mechanism of biological processes. Scientific questions can initially be addressed using computational modeling and simulation studies. The common feature in this work is to understand intermolecular interactions related to protein targets in the brain, as it relates to HIV infection and Alzheimer’s Disease. HIV is among the world’s most deadly infectious diseases. Recent therapeutic advancements have begun to increase the life expectancy of people living with this virus. The mechanisms that lead to neurobiological complications known as HIV- associated neurocognitive disorders (HAND), in HIV cases are not well understood. HIV- infected patients have displayed unusual synaptic levels of dopamine (DA) and led to reduced binding and function of monoamine transporters such as the norepinephrine transporter (NET), vesicular monoamine transporter (VMAT), and serotonin transporter (SERT). Allosteric modulators of the dopamine transporter (DAT) have been identified that can partially inhibit DA uptake and affect DAT-mediated release without affecting DAT binding.

Different approaches have been utilized to develop an accurate 3D model of the HIV-1 Tat and NET binding complex which would help reveal the mechanism for how HIV-1 Tat causes toxicity in the neurons by affecting DA uptake. The modeling results show that HIV-1 Tat-hNET binding is highly dynamic and HIV-1 Tat preferentially binds to hNET in an outward-open state. VMAT is related to NET as it transports a wide range of substrates including DA, norepinephrine (NE), and 5-HT. Binding modes are shown for HIV-1 Tat binding to SERT and VMAT, describing how HIV-1 Tat inhibits their function.

There is a significant need for new therapeutic compounds for the treatment of mental cognitive impairment (MCI) and Alzheimer's disease. Current therapies provide minimal symptomatic relief, without curing or halting MCI. Preclinical data have shown that Phosphodiesterase 2 (PDE2) can be targeted to improve memory in Alzheimer’s disease in mouse models and reverse some markers of neuropathology. PDE2 is an enzyme that hydrolyzes cGMP and is involved in memory and cognition. PDE2 is the most prevalent member of its family and is expressed in the hippocampus and frontal/temporal cortex regions. Clinical studies have not produced improved candidates due in part to suboptimal selectivity, poor metabolic stability, or limited brain penetrance. Currently there are no PDE2A inhibitors that are approved for clinical use. State-of-the-art drug discovery tools and techniques were used to discover novel inhibitors for PDE2A catalytic and allosteric binding sites. This is the first demonstration of novel compounds that target PDE2 at an allosteric site.

Digital Object Identifier (DOI)

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