Simulations Plus, Inc. · NASDAQ:SLP
Simulations Plus — Technical Presentation (September 2020)
22 slides from Simulations Plus's technical presentation, September 2020
Slide 1: ADMET Predictor 10.0 (APX) Release Webinar
ADMET Predictor® 10.0 (APX) Release Webinar
Slide 2: Outline
Outline • Introduction to ADMET Predictor • New Features in Version 10.0 • Software Demonstration
Slide 3: ADMET Predictor Overview
ADMET Predictor Overview Property Prediction PBPK Simulations Physicochemical %Fa, %Fb Metabolism Cmax, Tmax, AUC, T1/2, CL Transporters Cp-time curves Toxicity Optimal dose ADMET Risk Model Building Cheminformatics Activity, properties Compound design Molecular + atomic descriptors Scaffold cluster
Slide 4: Property Prediction: Methodology
Property Prediction: Methodology NIH SBIR Grants: - 1R43CA130388-1 - 2R44CA130388-02A1 pKa model Output Neurons Ensemble Descriptors Neurons
Slide 5: Outline
Outline • Introduction to ADMET Predictor • New Features in Version 10.0 • Software Demonstration
Slide 6: AIDD Module
AIDD Module Artificial Intelligence-Driven Drug Design New capabilities for evolutionary multi- objective compound optimization
Slide 7: Analog Generation Using Rules
Analog Generation Using Rules Apply transform rules to a lead compound Generated analogs Transform rules Starting structure Example analog • Bioisosteric replacements • Reactions from literature or in-house expertise • Chemically-intelligent “mutations” Users can modify the default rules
Slide 8: AIDD Methodology
AIDD Methodology • Builds on the transform-based analog generation approach, with improved and expanded rules • Incorporates property prediction: • ADMET, %Fa or %Fb, risks, user activity models • Incorporates Synthetic Difficulty scores • Uses iterative approach: in each generation the best analogs
Slide 9: AIDD Methodology
AIDD Methodology Ertl’s fragment-dictionary method Pareto-optimal compounds (3 layers) reasonably predicts synthetic difficulties reported by chemists Objective 2 Objective 1 Ertl et al., J. Cheminformatics. 2009 1:8
Slide 10: AIDD Workflow
AIDD Workflow Generate new Evaluate objectives: Initialize with one or compounds by Prune to a small more seed compounds ADMET transforming randomly- number of compounds and choose a set of selected compounds HTPK (%Fa, %Fb) by retaining only those objectives for from the current Risks that are Pare
Slide 11: Transporters Module
Transporters Module Adapted from Transporter-Mediated Drug-Drug Interactions (DDIs) https://www.fda.gov/ media/78640/download Advances in Chronic Kidney Disease, Vol 23, No 2 (March), 2016: pp 76-81.
Slide 12: Transporter Models in APX
Transporter Models in APX BCRP OATP1B1 | OATP1B3 ocT1 ocT2 OAT1 OAT3 | esep | is|+] SimulationsPlus SCIENCE + SOFTWARE = SUCCESS
Slide 13: HTPK Enhancements
HTPK Enhancements • Driven by collaboration with large pharmaceutical company • Support for longer/multiple dosing intervals • Expanded command-line options • Additional predicted PK parameters (T1/2, CL, CLplasma) • Further enhancements coming in 2021 Alternate front end based on command line
Slide 14: More New Features in APX
More New Features in APX • New Models – Hepatocyte clearance (human and rat) • Improved Models with New Data – Volume of distribution – Blood-brain barrier (BBB) classification – hERG blocker classification – hERG pIC50 – OATP1B1 inhibitor classification – Pgp substrate classification – Pgp inhibito
Slide 15: More New Features in APX
More New Features in APX • Expanded Parallelization – ADMET property predictions and PK simulations can now take advantage of multi-core CPUs – A roughly 4- to 5-fold speed improvement can be expected on a typical computer with 4 physical cores – An even greater speed improvement can be expected for
Slide 16: More New Features in APX
More New Features in APX Greater control over window text sizes
Slide 17: More New Features in APX
More New Features in APX Enhanced spreadsheet filtering controls
Slide 18: More New Features in APX
More New Features in APX Tooltips for predicted properties can be exported
Slide 19: More New Features in APX
More New Features in APX • Support for heteroatom stereocenters and hydrogen isotopes • Support for exporting version 3000 SD files • Improved license handling • Many more user-requested enhancements
Slide 20: Outline
Outline • Introduction to ADMET Predictor • New Features in Version 10.0 • Software Demonstration
Slide 21: AIDD Example
AIDD Example dx.doi.org/10.1021/jm301721e | J. Med. Chem. 2013, 56, 2690−2694
Slide 22: Thank You!
Thank You! www.simulations-plus.com info@simulations-plus.com
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