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Structure Based Design, Synthesis, Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Novel Cyclophilin D Inhibitors
journal contribution
posted on 2015-12-17, 01:12 authored by Koteswara
Rao Valasani, Jhansi Rani Vangavaragu, Victor W. Day, Shirley ShiDu YanCyclophilin D (CypD) is a peptidyl
prolyl isomerase F that 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 mitochondrial membrane permeability
transition pore (mPTP) leading to cell death and has been linked to
Alzheimer’s disease (AD). Because CypD interacts with amyloid
beta (Aβ) to exacerbate mitochondrial and neuronal stress, it
is a potential target for drugs to treat AD. Since appropriately designed
small organic molecules might bind to CypD and block its interaction
with Aβ, 20 trial compounds were designed using known procedures
that started with fundamental pyrimidine and sulfonamide scaffolds
know to have useful therapeutic effects. Two-dimensional (2D) quantitative
structure–activity relationship (QSAR) methods were applied
to 40 compounds with known IC50 values. These formed a
training set and were followed by a trial set of 20 designed compounds.
A correlation analysis was carried out comparing the statistics of
the measured IC50 with predicted values for both sets.
Selectivity-determining descriptors were interpreted graphically in
terms of principle component analyses. These descriptors can be very
useful for predicting activity enhancement for 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.
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Keywords
2 D QSARdrug candidatesdescriptoramyloid betacorrelation analysisMolecular dynamics simulations2 D QSAR studies20 trial compoundsVirtual Screening3 D pharmacophore models3 D pharmacophore modelIC 50 valuesdocking experimentssulfonamide scaffoldsCypD treatmentmitochondrial membranemitochondrial membrane permeability transition poreNovel Cyclophilin D InhibitorsCyclophilin D5 Lipinski criteriaMolecular Docking Studies5 Lipinski rulesPharmacophore Modelingmitochondrial membrane permeability transition40 compoundscell death20 moleculesIC 50principle component analysesADpeptidyl prolyl isomerase Fmitochondrial matrixactivity enhancement
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