OpenZika Nears End of Work on World Community Grid

Work ending on World Community Grid

Recently we evaluated the work that has been done for the OpenZika project, and came to the conclusion that we have nearly completed what we proposed to do—namely, to do virtual screening for nearly all Zika virus proteins from the largest dataset of compounds available (the ZINC 15 library, with approximately 30 million compounds). Thanks to the volunteers who supported the project, we have many, many results to evaluate.

Over the next few weeks, we’ll submit a few additional structures of the Zika virus and dengue virus NS5 polymerase (RNA and active site) and NS5 methyltransferase (GTP site) to finish our project. When the World Community Grid development team creates work units for these structures, this should create approximately 20,000 batches. Once these are completed, we will turn our full attention to analyzing the data.

Progress on selecting and testing compounds

We virtually screened the ChemBridge commercial database, with more than 1 million compounds, against Zika virus (ZIKV) proteins: envelope, protease, helicase, polymerase and methyltransferase. 

We also screened the ChemBridge database against dengue proteins protease and helicase. After the docking calculations on OpenZika, we ran the compounds through the free energy filter and the ZIKV machine learning models filter. We also performed a medicinal chemistry-based inspection of the most promising candidates. 

This new round of compounds allowed us to select 55 new candidates for Zika and 20 candidates for dengue. The compounds were purchased and sent to the University of California in San Diego at Dr. Jair Siqueira-Neto’s laboratory, for experimental evaluation. They are performing cell-based assays in human neural stem cells (hNSCs) with ZIKV. We will also perform enzymatic assays in ZIKV NS3 helicase and protease proteins with our collaborators at the Physics Institute of Sao Carlos, University of Sao Paulo (Brazil), at Dr. Glaucius Oliva’s laboratory, to validate the predicted enzymatic candidates’ activities. 

Additionally, we performed virtual screening of two in-house natural products and semi-synthetic compounds datasets from two collaborators: Dr. Laster at North Carolina State University (NC State University), and Dr. Regasini at São Paulo State University (UNESP). We virtually screened the compounds against ZIKV NS3 protease and helicase proteins and ran the compounds through the free energy filter. Afterwards, we performed a target prediction analysis of the promising hits. The extracted and isolated compounds were then tested using in vitro assays, cell-based assays and enzymatic assays, to validate the in silico study.

Status of the calculations

In total, we have submitted almost 8.57 billion docking jobs, which involved 427 different target sites. Our initial screens used an older library of 6 million commercially available compounds, and our current experiments utilize the new ZINC15 library of 30.2 million compounds. 

Thus far, the > 80,000 volunteers who have donated their spare computing power to OpenZika have given us > 84,711 CPU years’worth of docking calculations, at a current average of 75.1 CPU years per day!  Thank you all very much for your help!!

Except for a few stragglers, we have received all of the results for our experiments that involve docking 30.2 million compounds versus NS1, NS3 helicase (both the RNA binding site and the ATP site), NS5 RNA polymerase (NTP and RNA pocket), NS5 methyltransferase (SAM site), NS2B/NS3 protease, capsid (binding pockets 1 and 2) and envelope protein.  

Upcoming publications

We recently published a review entitled “High Throughput and Computational Repurposing for Neglected Diseases” in the journal Pharmaceutical Research. This paper describes the many drug repurposing efforts that have been going on in different labs around the world to try to find treatments for the many tropical diseases, including Zika and dengue infections.

OpenZika researchers Dr. Melina Mottin, Dr. Roosevelt Silva, Msc. Bruna Sousa and Paulo Ramos submitted abstracts for consideration for oral and/or poster presentation at the 9^thBrazMedChem2019 conference, the major medicinal chemistry conference in Latin America. Dr. Mottin and Bruna will present the studies related to natural compounds: “Discovery of flavonoids from Pterogyne nitens with potent activity against Zika virus protease and helicase” and “Discovery of new Zika virus candidates: natural products from Angelica keiskei with activity against NS2B-NS3 protease.” Paulo will present the work “Integrative Similarity analysis, Docking and Machine Learning models for identifying new Zika NS5 hits guided by dengue NS5 inhibitors.” Dr. Roosevelt will present the ZIKV NS1 molecular dynamics study: “Dynamic Behavior of dengue and Zika viruses NS1 protein reveals monomer-monomer interaction mechanisms and insights to rational drug design.”

Papers being written – to be submitted soon:

We are preparing the following papers regarding the exciting results of OpenZika project:

• One paper reporting the results (virtual and experimental) of the first round of compounds selected against ZIKV NS3 helicase that presented anti-ZIKV activity in human neural stem cells (hNSCs)
• Three papers reporting the great results from the virtual screening and experimental evaluation of natural products (two from Brazilian collaborations and one from NC State University collaboration), from plants from Brazil and traditional Chinese medicine, respectively, which presented anti-ZIKV activity, inhibiting ZIKV proteins protease and/or helicase
• One paper reporting the results for approved drugs/clinical collections compounds, that have anti-malarial and anti-Ebola activity, that presented anti-ZIKV activities against ZIKV helicase protein, candidates for drug repurposing
• One paper reporting the computational results of ZIKV NS1 protein molecular dynamics simulations and insights regarding binding pockets and drug design. This paper has been submitted to Journal of Biomolecular Structure & Dynamics, titled “Dynamic Behavior of Dengue and Zika viruses NS1 protein reveals monomer-monomer interaction mechanisms and insights to rational drug design”, and is under consideration for publication.
• The team has also collaborated on a chapter for a book on trypanosomal diseases to be published in Burger’s Medicinal Chemistry.

These papers will be soon submitted to high-impact scientific journals.

Past publications and outreach

Our Drug Discovery Today keynote review “The A–Z of Zika drug discovery” was published on June 20 2018. This is a comprehensive review of the recent advances in ZIKV drug discovery efforts, highlighting drug repositioning and computationally guided compounds, including recently discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial for advancing the fight against the Zika virus and other flaviviruses, but it will also help the scientific community prepare for the next emerging virus outbreak to which we will have to respond.

Our paper “Computational drug discovery for the Zika virus” was published in a special issue of the Brazilian Journal of Pharmaceutical Sciences. In this paper, we summarize current computational drug discovery efforts and their application to the discovery of anti-ZIKV drugs. We also present successful examples of the use of computational approaches to ZIKV drug discovery, including our OpenZika project.

Dr. Sean Ekins presented a poster at Cell Symposia: Emerging and Re-emerging Viruses, on October 1-3, 2017, in Arlington, VA, USA, titled “OpenZika: Opening up the discovery of new antiviral candidates against Zika virus”.

Our PLoS Neglected Tropical Diseases paper, "OpenZika: An IBM World Community Grid Project to Accelerate Zika Virus Drug Discovery,"was published on October 20 2016, and it has already been viewed over 5,200 times. Anyone can access and read this paper for free. Another research paper “Illustrating and homology modeling the proteins of the Zika virus” was published in F1000Research and viewed > 4,200 times. 

We have also published another research paper entitled “Molecular Dynamics simulations of Zika Virus NS3 helicase: Insights into RNA binding site activity” in a special issue on flaviviruses for the journal Biochemical and Biophysical Research Communications. This study of the NS3 helicase system helped us learn more about this promising target for blocking Zika replication. The results will help guide how we analyze the virtual screens that we performed against NS3 helicase, and the molecular dynamics simulations generated new conformations of this system that we have been using as targets in new virtual screens that we performed as part of OpenZika.

The OpenZika project results were presented at the 256th ACS National Meeting, on August 19-23, 2018,  in Boston, MA, USA. Dr. Mottin gave an oral presentation and presented a poster entitled “OpenZika: Discovery of new antiviral candidates against Zika virus,; in the session “Chemoinformatics Approaches to Enhance Drug Discovery Based on Natural Products.”

Dr. Mottin also gave an oral presentation “Applying Molecular Dynamics to Drug Discovery for Zika Virus and Schistosoma mansoni,” in the South American Initiative for Cooperation on Molecular Simulations (SAIMS) meeting, held at Institut Pasteur, Montevideo, Uruguay, November 4-7, 2018.The meeting was a great opportunity to exchange experiences and collaborate with South American researchers who work with Zika.

Information about BrazMedChem

The Principal Investigator of OpenZika, Prof. Carolina Horta Andrade, also Director of the Medicinal Chemistry Division of the Brazilian Chemical Society (SBQ), is organizing the major medicinal chemistry & drug discovery conference in Latin America, the 9^thBrazMedChem2019, to be held September 1-4, 2019, in Pirenópolis, Goias, Brazil.

The main theme of this year’s conference is "Bridging the gap between Academia and Pharmaceutical Industries for Advancing Drug Discovery." The Organizing and Scientific Committees are working to keep the outstanding quality of the past editions, trying to enable the effective engagement and participation of the scientific community, in a modern structure that mixes high level science and social activities to congregate participants.

We expect to host around 500 people, mainly graduate students, researchers and professors working in the field of medicinal chemistry from Brazil and Latin American countries, in an interactive and collaborative atmosphere to exchange of experiences and information to meet the challenges of the medicinal chemistry of the 21^st century. 

Moreover, Dr. Sean Ekins, co-PI of the OpenZika project, is going to 9^thBrazMedChem to give a talk regarding our work on OpenZika as well as on his work on Chagas disease and Ebola drug discovery, which represents just a few of the neglected disease collaborations he is involved with. 

New project team members

Paulo Ramos is a new undergraduate student who joined Prof. Andrade’s laboratory in January 2019. In his project work, he first searched for dengue virus (DENV) NS5 inhibitors in the PubChem and ChEMBL databases. He also performed an integrative similarity analysis of dengue and Zika NS5 proteins, docking of DENV known inhibitors on Zika NS5 sites and machine learning (ML) models, to prioritize the best hits. He found 156 compounds reported as dengue NS5 inhibitors, that were docked in the Zika NS5 sites and scored by ML models. Twenty-two compounds were selected as showing the best results. Then, he performed a similar search with the hits in a commercial database (e-molecules) and screened the similar compounds using the docking and ML filters. The 67 virtual hits for Zika NS5 will be validated by cell-based Zika assays.

In Dr. Ekins’ lab, Kim and Daniel have been involved in scoring compounds for the OpenZika projects with our machine learning models developed for different datasets. Collaborations Pharmaceuticals continues to address neglected diseases through collaborations with scientists around the world. If you would be interested in collaborating with us, please contact sean@collaborationspharma.com.

We are incredibly grateful for all the volunteers who are donating their unused computing time to this project!  Thank you very much!!