Park, Insun Londhe, Ashwini M. Lim, Ji Woong Park, Beoung-Geon Jung, Seo Yun Lee, Jae Yeol Lim, Sang Min No, Kyoung Tai Lee, Jiyoun Pae, Ae Nim 2024-01-20T00:31:24Z 2024-01-20T00:31:24Z 2021-09-05 2017-10 0920-654X https://pubs.kist.re.kr/handle/201004/122212 Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to beta amyloid (A beta) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD). In this study, we generated an energy-based pharmacophore model by using the crystal structure of CypD-cyclosporine A (CsA) complex and performed virtual screening of ChemDiv database, which yielded forty-five potential hit compounds with novel scaffolds. We further tested those compounds using mitochondrial functional assays in neuronal cells and identified fifteen compounds with excellent protective effects against A beta-induced mitochondrial dysfunction. To validate whether these effects derived from binding to CypD, we performed surface plasmon resonance (SPR)-based direct binding assays with selected compounds and discovered compound 29 was found to have the equilibrium dissociation constants (K-D) value of 88.2 nM. This binding affinity value and biological activity correspond well with our predicted binding mode. We believe that this study offers new insights into the rational design of small molecule CypD inhibitors, and provides a promising lead for future therapeutic development. English SPRINGER PERMEABILITY TRANSITION PORE CELL-DEATH BINDING IDENTIFICATION IMMUNOPHILINS SCLEROSIS ISOMERASE COMPONENT DOCKING DISEASE Discovery of non-peptidic small molecule inhibitors of cyclophilin D as neuroprotective agents in A beta-induced mitochondrial dysfunction Article 10.1007/s10822-017-0067-9 1 JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, v.31, no.10, pp.929 - 941 JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 31 10 929 941 scie scopus 000413448900006 2-s2.0-85029545137 Biochemistry & Molecular Biology Biophysics Computer Science, Interdisciplinary Applications Biochemistry & Molecular Biology Biophysics Computer Science Article PERMEABILITY TRANSITION PORE CELL-DEATH BINDING IDENTIFICATION IMMUNOPHILINS SCLEROSIS ISOMERASE COMPONENT DOCKING DISEASE Cyclophilin D (CypD) Small molecule inhibitors Mitochondrial permeability transition pore (mPTP) Alzheimer&apos s disease (AD) Energy-based pharmacophore Molecular docking Virtual screening