EXPLORING BINDING MODES OF BENZTROPINE-LIKE INHIBITORS OF DOPAMINE TRANSPORTER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A development grant of 30,000 SU is requested to run molecular dynamics simulation of benztropine (BZT) with the dopamine transporter (DAT) in explicit membrane and water. The long term goal of the project is to derive the binding modes of BZT-like inhibitors, understand their structure-activity relationship (SAR) in the context of the DAT structure and design inhibitors without psycho-stimulating effects. Highly selective and potent BZT-like DAT inhibitors differ from cocaine-like inhibitors that they exhibit less euphoric effects and thus show promises in developing into anti-cocaine therapeutic agents. BZT-like inhibitors have very different SAR than cocaine-like inhibitors. However, it has never been understood the structural basis for their different SAR. We will investigate the binding modes of BZT analogues to gain structural insights into the SAR of BZT which will help us to design inhibitors without euphoric effects. We request computational time on IU e1350 (Big Red), NCSA Altix (Cobalt) or TACC PowerEdge 1955 (Lonestar) to run simulations by using NAMD. The choice of machine is made based on NAMD Benchmarks (http://www.ks.uiuc.edu/Research/namd/performance.html) which shows that these machines run much faster than other machines on a system of 92K atoms with up to 128 processors by using NAMD 2.6. Our system has about 88K atoms. The equilibration (3 nanoseconds) and production (10 nanoseconds) stages will approximately take 2000 and 7000 SU, respectively. We will test the above machines to compare which runs faster for our system. Then promising binding modes of BZT produced by a simulated-annealing docking protocol will be equilibrated and then the most promising binding modes will be studied by the 10ns production run.