Perturbation Modeling for Molecular Design of Protein Tyrosine Kinase Inhibitors using Unsupervised Machine Learning

Author

Keerthi Krishnan, Chapman UniversityFollow

Date of Award

Summer 8-2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Computational and Data Sciences

First Advisor

Gennady Verkhivker

Second Advisor

Cyril Rakovski

Third Advisor

Mohamed Allali

Abstract

The field of computational drug discovery and development has grown, with the aid of new computational tools for novel molecule discovery. In specific, generative deep learning models have excelled as tools to aid in navigating the large space of known molecules and in the creation of new molecules. These models are fed various representations of molecules as inputs and learn to perform a variety of things, such as the optimization of these molecules towards a targeted property. Ultimately, these generative learning models allow us to build bridges between chemical and continuous spaces to understand the compromise between invoking small incremental changes to radical modifications and generate optimal molecules for therapeutic benefits. The goal of this study pertains to creating a perturbation modeling framework in which we can conduct transformations of small molecules to SRC kinase inhibitors using a combination of a generative learning technique called Variational Auto-Encoders and Unsupervised Machine Learning techniques. This study focuses specifically using the methods above to transform molecules from various kinase inhibitor families to SRC Kinase Inhibitors. These generated molecules are evaluated using various physicochemical metrics and similarity metrics for validity of transformation. The results of this study demonstrate that Machine Learning based perturbation techniques can aid in the evolution of molecules from one chemical space to another. By combining Generative Learning frameworks with targeted based alteration of the continuous space, we allow for the emergence of novel molecules that are structurally adjacent to the various molecular scaffolds of SRC Kinase Inhibitors. Our findings also suggested that these vi molecules exhibit chemical and drug-likeness similarity to known SRC Kinase Inhibitors, displaying potential for synthetic and therapeutic benefits. Further studies should be conducted to determine whether the novel molecules that are generated contain potential to be synthesized for practical use.

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Recommended Citation

K. Krishnan, "Perturbation modeling for molecular design of protein tyrosine kinase inhibitors using unsupervised machine learning," M. S. thesis, Chapman University, Orange, CA, 2022. https://doi.org/10.36837/chapman.000397