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Computational studies on molecular mechanisms for dysregulation of monoamine transporters by HIV-1 Tat and drug discovery of novel phosphodiesterase-2 inhibitors

CP 114
Speaker(s) / Presenter(s):
Charles Adeniran

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 in HIV cases are not well understood. HIV infection in macrophages results in HIV-1 Tat proteins being released and impairing the function of monoamine transporters. HIV-infected patients have displayed unusual synaptic levels of neurotransmitters and led to reduced binding and function of monoamine transporters such as the norepinephrine transporter, vesicular monoamine transporter, and serotonin transporter.   Here we use different approaches to develop an accurate three-dimensional model of the HIV-1 Tat and NET binding complex which would help reveal how HIV-1 Tat causes toxicity in the neurons by affecting 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. VMAT2 is related to NET as it transports a wide range  of  substrates  including dopamine, norepinephrine, and serotonin. HIV-1 Tat affects VMAT2 similarly to NET, binding and inhibiting its function. VMAT2 is also inhibited by a number of small molecules and the binding modes are explored. The neurobiological mechanisms underlying HIV-associated depression are not well understood. Depression severity in HIV cases has been linked to acute and chronic markers of systemic inflammation and relates to serotonin levels. HIV-1 Tat affects the serotonin reuptake mechanism by inhibiting the serotonin transporter. Here we explore the possible binding modes of HIV-1 Tat and SERT. There are also a number of substrates that inhibit SERT normal function and the binding of HIV-1 Tat-SERT complex. The binding modes of these complexes are also explored here.   There is a significant need for new therapeutic compounds for the treatment of cognitive dysfunction. Current therapies provide minimal symptomatic relief, without curing or halting cognitive impairment. Preclinical data have shown that inhibitors of cyclic nucleotide phosphodiesterase 2 improve memory in Alzheimer’s disease mouse models and reverse some markers of neuropathology. Family members of PDE, notably PDE4 and PDE5, have been shown to be druggable targets and suggest the same can apply to PDE2. PDE2A is the most prevalent of the family and is expressed in the hippocampus and frontal/temporal cortex regions. PDE2 is a dual specific enzyme that hydrolyzes cGMP and cAMP, and is involved in memory and cognition and is susceptible to Alzheimer’s disease associated neuropathology. 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. Here we utilize state-of-the-art drug discovery tools and techniques to discover, design, and optimize novel and drug-like inhibitors for PDE2A. The discovery schema for novel, potent and selective PDE2A inhibitors will use a proven, iterative process where outcomes of in vitro and in vivo testing informs and guides modeling and medicinal chemistry.

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