title: Integrated Computational Approach for Virtual Hit Identification against Ebola Viral Proteins VP35 and VP40.
abstract: The Ebola virus (EBOV) has been recognised for nearly 40 years, with the most recent EBOV outbreak being in West Africa, where it created a humanitarian crisis. Mortalities reported up to 30 March 2016 totalled 11,307. However, up until now, EBOV drugs have been far from achieving regulatory (FDA) approval. It is therefore essential to identify parent compounds that have the potential to be developed into effective drugs. Studies on Ebola viral proteins have shown that some can elicit an immunological response in mice, and these are now considered essential components of a vaccine designed to protect against Ebola haemorrhagic fever. The current study focuses on chemoinformatic approaches to identify virtual hits against Ebola viral proteins (VP35 and VP40), including protein binding site prediction, drug-likeness, pharmacokinetic and pharmacodynamic properties, metabolic site prediction, and molecular docking. Retrospective validation was performed using a database of non-active compounds, and early enrichment of EBOV actives at different false positive rates was calculated. Homology modelling and subsequent superimposition of binding site residues on other strains of EBOV were carried out to check residual conformations, and hence to confirm the efficacy of potential compounds. As a mechanism for artefactual inhibition of proteins through non-specific compounds, virtual hits were assessed for their aggregator potential compared with previously reported aggregators. These systematic studies have indicated that a few compounds may be effective inhibitors of EBOV replication and therefore might have the potential to be developed as anti-EBOV drugs after subsequent testing and validation in experiments in vivo.
authors: Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Defense Road, Lahore 54000, Pakistan. usmanmirzapk@yahoo.com.|Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan. usmanmirzapk@yahoo.com.
authors: Muhammad Usman
authors: MU
authors: Mirza
authors: Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore 54000, Pakistan. naxiaikram@gmail.com.
authors: Nazia
authors: N
authors: Ikram
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D029043:Ebolavirus / Q000187:drug effects* / Q000378:metabolism; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000821:virology; D006801:Humans; D062105:Molecular Docking Simulation; D016415:Sequence Alignment; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C080980:VP35 protein, filovirus; C080981:VP40 protein, virus; D014763:Viral Matrix Proteins; D054334:Viral Regulatory and Accessory Proteins
keywords: Ebola virus; VP35; VP40; molecular docking; phytochemicals; retrospective validation; virtual screening