Revolutionizing Drug Discovery: The Impact of Orpheus in Drug Development

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The world of drug discovery is a challenging and resource-intensive pursuit, demanding precision and innovation. Researchers face the complexities of identifying active compounds targeting pathogenic proteins. They initiate this process by seeking these active drugs (hits) and later fine-tuning them through lead optimization. This intricate method crucially addresses a drug’s absorption, distribution, metabolism, excretion, and toxicity. 

Within this process, Computer-Aided Drug Discovery (CADD) emerges as a vital accelerator, employing techniques like structure-based virtual screening for precise compound recognition. 

Yet, the landscape evolves with the advent of this groundbreaking 3D convolutional neural network application and a comprehensive knowledge graph called Orpheus.

In this article, we will discover the role of Wisecube’s Orpheus in drug discovery, its distinctive features, associated benefits, and practical insights for leveraging this innovative knowledge graph within your organization. 

What is Orpheus?

Orpheus is Wisecube’s pioneering 3D convolutional neural network application built on a comprehensive biomedical knowledge graph. It is trained on an extensive repository of crystal structures to systematically predict molecular fingerprints for missing fragments within co-crystallized ligands. Remarkably, it achieves an impressive 60% accuracy in matching missing fragments from a library of around 6,500 fragments.

Notably, Orpheus doesn’t stop at replacement; it excels by suggesting chemically similar alternatives, sometimes presenting even more optimal solutions. Employing advanced AI and deep learning, this innovative tool predicts bioactivity and around 30 ADMET properties, enabling scientists to craft custom models from experimental data. By rapidly identifying the most promising compounds, Orpheus drastically reduces drug discovery timelines, marking a new era of efficient therapeutic development.

What is the Role of Orpheus in Drug Development?

Orpheus stands as a crucial and innovative tool in drug discovery, revolutionizing the early stages of drug development. Its transformative capabilities extend beyond conventional methods, offering a unique approach to enhancing the efficiency of therapeutic solution development. Here are some of its key functions:

  • Predicting molecular fingerprints for missing fragments with 60% accuracy.
  • Introducing novel fragments to existing leads, revealing chemical similarities.
  • Enhancing lead optimization through AI predictions and tailored training, vital for novel medical solutions.
  • Accelerating compound identification through advanced AI and deep learning.
  • Conducting in-silico compound analysis, predicting bioactivity and around 30 ADMET properties, enhancing efficiency.

Decoding Orpheus’s Mechanism

Empowering organizations to create custom models and obtain accurate predictions for future compounds is crucial. Here is a breakdown of Orpheus’s mechanism to help you explore how this innovative tool works.

Ligand Extension with Molecular Fragments

Orpheus functions by extending a ligand with a molecular fragment, ensuring a highly complementary extension to the receptor. This process is essential for enhancing the effectiveness and specificity of potential drug compounds.

Importance of Lead Optimization

Lead optimization is a strategic chemical alteration applied to a small-molecule ligand, aiming to enhance essential properties like binding affinity. Orpheus, functioning as an advanced deep-learning model, excels in providing recommendations for these modifications.

Orpheus as a Browser-Based App

Designed for universal accessibility, Orpheus functions as a browser-based app. Its intuitive graphical interface runs Orpheus models on the server side, eliminating the need for separate third-party software installation.

What are the Unique Features of Wiscube’s Orpheus?

Wisecube’s Orpheus stands out with unique features that streamline drug development’s initial phases, encompassing practical functionalities. Its notable attributes include:

1. Built on the largest Biomedical Knowledge base

Orpheus leverages a comprehensive biomedical knowledge graph for enhanced drug discovery. Drawing from diverse biomedical data, this rich repository empowers Orpheus to conduct insightful analyses, improving predictions for bioactivity, ADMET properties, and drug interactions. 

2. Deep Learning-based Lead Optimization

Orpheus, at its core, employs a sophisticated deep convolutional Foundational Graph AI model for advanced ligand optimization. It intelligently extends ligands with molecular fragments, ensuring high complementarity to the target receptor and enhancing the lead optimization process.

3. Custom Model Training

Customizing models for specific therapeutic areas is crucial due to the target and data dependency of bioactivity. Orpheus enables scientists to achieve this independently, utilizing a unique AI methodology for self-service, eliminating the need for extensive data science teams.

4. Visual Analysis Features

Orpheus incorporates robust visual analysis features, allowing drug discovery scientists to explore model predictions visually and identify promising compounds. The custom review and analysis feature facilitates asynchronous discussions on the merits of shortlisted compounds.

5. Out-of-the-box ADMET Models in Orpheus

Orpheus comes equipped with pre-built ADMET models, providing users with ready-to-use predictions for absorption, distribution, metabolism, excretion, and toxicity properties. This feature streamlines the assessment of a compound’s pharmacokinetic and safety profile, enhancing efficiency in drug development.

LogSBasic physicochemical propertyThe log of aqueous solubility value
LogD7.4Basic physicochemical propertyThe log of the n-octanol/water distribution coefficients at pH=7.4
Caco2AbsorptionCaco-2 cell permeability
PGPiAbsorptionThe inhibitor of P-glycoprotein
PGPsAbsorptionThe substrate of P-glycoprotein
HIAAbsorptionThe human intestinal absorption
F (20%)AbsorptionThe human oral bioavailability. (20%)
F (30%)AbsorptionThe human oral bioavailability. (30%)
PPBDistributionThe plasma protein binding
VDDistributionThe volume of distribution
BBBDistributionThe blood brain barrier
CYPIA2iMetabolismCYP 1A2-Inhibitor
CYPIA2sMetabolismCYP 1A2-substrate
CYP3A4iMetabolismCYP 3A4-Inhibitor
CYP3A4sMetabolismCYP 3A4-Substrate
CYP2C9iMetabolismCYP 2C9-Inhibitor
CYP2C9sMetabolismCYP 2C9-Substrate
CYP2CI9iMetabolismCYP 2C19-Inhibitor
CYP2C19sMetabolismCYP 2C19-Substrate
CYP2D6iMetabolismCYP 2D6-Inhibitor
CYP2D6sMetabolismCYP 2D6-Substrate
CLExcretionThe clearance of a drug
T-HALFExcretionThe half-life of a drug
hERGToxicityThe human ether-a-go-go related gene
H-HTToxicityhuman hepatotoxicity
AmesToxicityAmes test for mutagenicity
DILIToxicityDrug-induced liver injury
FDAMDDToxicitymaximum recommended daily dose
SkinSToxicitySkin Sensitivity
ROATToxicityRat oral acute toxicity

What are the Benefits of Using Orpheus?

Orpheus emerges as a transformative tool, driving drug discovery into a new era of efficiency in therapeutic solution development. Here are some critical benefits that are worth considering;

  • Advanced AI and Deep Learning: Orpheus utilizes cutting-edge technologies to forecast bioactivity and around 30 ADMET properties, simplifying in-silico compound analysis and lead optimization.
  • Custom Model Training for Enhanced Accuracy: Scientists can craft models customized to their experimental data, improving accuracy in predictions and activity forecasts.
  • Time Efficiency in Drug Discovery: Orpheus’s swift identification of viable compounds markedly accelerates the drug discovery and design workflow.

How to Utilize Wisecube’s Orpheus?

Organizations can use Orpheus for revolutionary drug discovery. Let’s explore how to leverage Wisecube’s Orpheus effectively for enhanced outcomes.

Orpheus Browser App

This intuitive, web-based application requires no setup, providing scientists with a straightforward way to tap into Orpheus’s capabilities.

Orpheus API for Customized Tasks

The Orpheus API offers precise control over predictions for tailored tasks, enabling users to engage directly with raw data structures and AI models. A practical Google Colab (Jupyter Notebook) example demonstrates manual prediction processes.

Interactive Notebook for Virtual Screening

This feature expedites drug discovery by enabling scientists to virtually screen compounds, predicting bioactivity and ADMET properties for small molecules.

How Wisecube Helped IDRI in Overcoming Error-Prone Ligand-Based Virtual Screening for TB?

IDRI (Infectious Disease Research Institute), based in Seattle, is a non-profit biotech organization dedicated to comprehensively addressing infectious diseases. Merging rigorous scientific research with the product development capabilities of a life science company, IDRI integrates academia’s quality with an onsite GMP manufacturing facility.

IDRI’s Problem

IDRI encountered challenges in its R&D process as utilizing out-of-the-box QSAR models for ligand-based virtual screening against TB targets proved error-prone. The lack of customization to their dataset rendered these models essentially random, causing significant delays in IDRI’s research and development endeavors.

Wisecube’s Solution 

Wisecube introduced a tailored approach leveraging its cutting-edge technology, Orpheus. This multifaceted solution was designed to align with the specific datasets and research requirements of IDRI, marking a crucial advancement in addressing the complexities of TB drug discovery.

1. Custom Virtual Screening: Orpheus on Nephos

Wisecube, in response to IDRI’s challenges, introduced a customized solution that revolutionized the drug discovery process. Leveraging the on-premise AI platform, Nephos, Wisecube implemented Orpheus, a custom virtual screening tool designed to address the specific needs of IDRI’s dataset. 

This innovative solution goes beyond traditional methods, offering a tailored approach for efficient and targeted virtual screening.

2. Custom ML Models for Training Scientists

As part of Wisecube’s commitment to empowering scientists, we integrated custom machine-learning models into the solution. These models adapted to the unique data distribution of IDRI, provided accurate predictions, and gave scientists the autonomy to train their own models. This dual approach enhances the overall flexibility and effectiveness of the drug discovery process, marking a significant step forward in virtual screening and model training.

Wisecube’s Orpheus played a significant role in enhancing the accuracy and efficiency of IDRI’s TB drug discovery process. By seamlessly integrating advanced AI, intuitive interfaces, comprehensive lead optimization, and ADMET modeling, Orpheus emerged as a transformative force in overcoming IDRI’s drug discovery challenges.

Reshaping the Future of Drug Discovery With Wisecube’s Orpheus

By leveraging Orpheus’s capabilities, IDRI tailored its research with custom models, leading to more precise predictions and faster development times. This collaboration exemplifies how Wisecube’s Orpheus can help organizations overcome traditional hurdles in drug discovery, setting a new standard for rapid, targeted, and effective therapeutic development. The success story with IDRI highlights the impactful role of Orpheus in advancing drug discovery and fostering innovation within the field.

If you are ready to explore the future of drug discovery with Orpheus, schedule a demo with Wisecube today!

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