A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus.

Sean Ekins,Joel S Freundlich,Megan Coffee

doi:10.12688/f1000research.5741.2

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.

Highlights

The current Ebola virus (EBOV) crisis has demonstrated that globally we are not prepared to respond with therapeutics to treat existing infections or act as prophylactics as there is no Food and Drug Administration (FDA) or European Medicines Agency (EMEA) approved therapeutic
These independent reports suggested the promise of the antimalarials amodiaquine and chloroquine in one study8, while the selective estrogen receptor modulators (SERMs) clomiphene and toremifene were active in another9
With the limited knowledge of small molecules and potential targets we have studied whether the FDA-approved drugs that are active in vitro and in vivo versus EBOV could be targeting viral protein 35 (VP35)

Summary

Introduction

The current Ebola virus (EBOV) crisis has demonstrated that globally we are not prepared to respond with therapeutics to treat existing infections or act as prophylactics as there is no Food and Drug Administration (FDA) or European Medicines Agency (EMEA) approved therapeutic More importantly this suggests we should have been prepared for a pathogen which has been known about for nearly forty years. Two recent studies utilized high-throughput screens of a subset of FDA approved drugs against different EBOV strains (Zaire and Sudan) in vitro and in vivo These independent reports suggested the promise of the antimalarials amodiaquine and chloroquine in one study, while the selective estrogen receptor modulators (SERMs) clomiphene and toremifene were active in another. The previous studies were not exhaustive screens of all FDA drugs and so we have taken this opportunity to suggest additional compounds Looked at from another perspective “non-antiviral” drugs may be worth following up even though their molecular mechanism is unknown. These compounds may themselves have broad antiviral activity as reports describe modest inhibitory activity against other viruses

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