These descriptors can be very useful for predicting activity enhancement for lead compounds. lead compounds. A 3D pharmacophore model was also created. Molecular dynamics simulations were carried out for the 20 trial compounds with known IC50 values, and molecular descriptors were determined by 2D QSAR studies using the Lipinski rule-of-five. Fifteen of the 20 molecules satisfied all 5 Lipinski rules, and the remaining 5 satisfied 4 of the 5 Lipinski criteria and nearly satisfied the fifth. Our previous use of 2D QSAR, 3D pharmacophore models, and molecular docking experiments to successfully predict activity indicates that this can be a very powerful technique for screening large numbers of new compounds as active drug candidates. These studies will hopefully provide a basis for efficiently designing and screening large numbers of more potent and selective inhibitors for CypD treatment of AD. 1.?Introduction Alzheimers disease (AD) is the most common cause of dementia in adults, resulting in a disorder of cognition and memory due to neuronal stress and eventuating in cell death. Current research indicates that mitochondrial and synaptic dysfunction is an early pathological feature of an AD affected brain.1?5 Mitochondrial amyloid- (A) accumulation in synaptic mitochondria has been shown to impair mitochondrial structure and function. A accumulation also has been shown to influence calcium homeostasis, energy metabolism, membrane potential, membrane permeability transition pore (mPTP), mitochondrial dynamics, respiration, and oxidative stress.6?11 Preventing and/or halting AD at its earliest stages may be possible by suppressing A-induced mitochondrial toxicity.12 Blocking A production or developing A inhibitors are two possible approaches. Other strategies might include developing inhibitors that block the clipping action of secretases,13?20 compounds that interfere with A oligomerization,21?23 and passive vaccines designed to clear amyloid directly.13 To date, none of these approaches have been shown to dramatically improve AD symptoms or protect brain cells and no drugs have entered clinical trials due to concerns about side effects. Because AD is a multifaceted disease and its molecular biology is poorly understood, multitargeted approaches for AD treatment should be more effective. Cyclophilin D (CypD), a peptidyl prolyl isomerase F, resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition. CypD plays a central role in opening the mPTP leading to cell death. The level of CypD was significantly elevated in neurons in AD-affected regions. We have shown that CypD forms a complex with A (CypDCA) that is present in the cortical mitochondria of AD brain and transgenic mice overexpressing human mutant form of amyloid precursor protein and A (Tg?mAPP). Surface plasmon resonance (SPR) has been used to show a high binding of recombinant CypD protein to A. When CypD was not present, A-mediated mitochondrial and synaptic dysfunction was reduced.6,24 Although the precise role of A Rabbit Polyclonal to NSE in mitochondria is not yet defined, reports illustrate that an interaction between mitochondrial 5-BrdU A and mitochondrial proteins, such as CypD, exacerbates mitochondrial and neuronal stress in 5-BrdU transgenic AD mouse models.6,8,24,25 These reports support the use of CypD a potential target for drug development in the treatment of AD. Blockade of CypD protects against A- and oxidative stress-induced mitochondrial and synaptic degeneration and 5-BrdU improves mitochondrial and cognitive function. To date, the most specific inhibitor of the.
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