title: A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus.
abstract: We are currently faced with a global infectious disease crisis which has been anticipated for decades. While many promising biotherapeutics are being tested, the search for a small molecule has yet to deliver an approved drug or therapeutic for the Ebola or similar filoviruses that cause haemorrhagic fever. Two recent high throughput screens published in 2013 did however identify several hits that progressed to animal studies that are FDA approved drugs used for other indications. The current computational analysis uses these molecules from two different structural classes to construct a common features pharmacophore. This ligand-based pharmacophore implicates a possible common target or mechanism that could be further explored. A recent structure based design project yielded nine co-crystal structures of pyrrolidinone inhibitors bound to the viral protein 35 (VP35). When receptor-ligand pharmacophores based on the analogs of these molecules and the protein structures were constructed, the molecular features partially overlapped with the common features of solely ligand-based pharmacophore models based on FDA approved drugs. These previously identified FDA approved drugs with activity against Ebola were therefore docked into this protein. The antimalarials chloroquine and amodiaquine docked favorably in VP35. We propose that these drugs identified to date as inhibitors of the Ebola virus may be targeting VP35. These computational models may provide preliminary insights into the molecular features that are responsible for their activity against Ebola virus in vitro and in vivo and we propose that this hypothesis could be readily tested.
authors: Collaborations in Chemistry, Fuquay-Varina, NC, 27526, USA ; Collaborative Drug Discovery, Burlingame, CA, 94010, USA.
authors: Sean
authors: S
authors: Ekins
authors: Departments of Pharmacology & Physiology and Medicine, Center for Emerging and Reemerging Pathogens, UMDNJ - New Jersey Medical School, NJ, 07103, USA.
authors: Joel S
authors: JS
authors: Freundlich
authors: Center for Infectious Diseases and Emerging Readiness, University of California, Berkeley, CA, 94720, USA.
authors: Megan
authors: M
authors: Coffee
keywords: computational models; ebola virus; machine learning