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Inter-molecular Binding Affinity Synthetic Data Augmentation Transforms the Landscape of Computational Biomolecule Design and Discovery

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Wei Li  *

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23 August 2024

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23 August 2024

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Abstract
The advancement of computational drug discovery and design necessitates continuous innovation to enhance the accuracy and scope of predictive models for early-stage drug research and development. This article introduces a novel workflow for in silico generation of structural and intermolecular binding affinity data with reasonable accuracy, combining two computational tools: Modeller and Prodigy. By leveraging synthetic structural and biophysical data, this approach addresses the limitations of existing experimental datasets, generating extensive, high-quantity binding affinity data with reasonable accuracy for biomolecular binding pairs, which broadens the horizon of computational biomolecule design and discovery by enabling extensive exploration of the sequence space of biomolecular binding pairs, and narrows the gap between experimental binding affinity data and its unexplored territories. Overall, this article presents a methodological advance to enhance the accuracy and scope of computational biomolecule discovery and design, paves the way for the development of preclinical candidates with improved efficacy and specificity, and holds transformative potential for further advancements in artificial intelligence-enabled biomolecule discovery and design in the future.
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Subject: Biology and Life Sciences  -   Biophysics

1. Background and Motivation

Development of a single novel small molecule drug takes up to 14-15 years and costs over 2.5 billion U.S. dollars from target assessment to regulatory approval [1,2,3]. To date, early-stage drug discovery and design remains an extremely costly and time-consuming process with rather high failure rate, yet it still is essential to ensure safety, quality and profitability of new therapeutic entities entering the market [4]. Historically, drug discovery and design have evolved significantly with the advent of computational methodologies, which have accelerated the identification and optimization of therapeutic candidates [5,6]. Traditional approaches, often involving labor-intensive and time-consuming experimental procedures [7], are increasingly supplemented by computational techniques that predict molecular interactions, binding affinities, and potential off-target effects with high accuracy [8,9,10].
In computational drug discovery and design, a critical task is accurate prediction of drug-target binding affinity [11,12,13], which is crucial for identification and continued optimization of potential drug candidates [14]. However, the availability and quality of experimental binding affinity data [11,15] are often the performance- and speed-limiting factors of these computational models [16,17,18,19,20]. Therefore, this article reports a novel workflow of in silico generation of structural and intermolecular binding affinity data with reasonable accuracy, aiming at improving the accuracy and scope of computational structural biophysics-based biomolecule design, and contributing a little bit to the development of accurate, efficient and cost-effective structural biophysics- and AI-enabled biomolecule discovery and design in future [2].

2. Modigy: a Computational Structural Biophysics-Based Workflow

Abbreviated as Modigy (Figure 1), the workflow involves two steps: homology structural modeling using Modeller [21] based on experimental complex structures from Protein Data Bank (PDB) [22] and physics-based calculations of intermolecular Kd using Prodigy [23,24], as illustrated in Figure 1 and described previously in detail [25].

3. How Does the Modigy Workflow Contribute to Biomolecular CADD?

By definition, biomolecule represents any of numerous substances that are produced by cells and living organisms [26,27]. In this article, the term biomolecule specifically refers to recombinant proteins, peptides, monoclonal antibodies, antibody- or peptide-drug conjugates [28,29,30,31,32]. Thus, for computational biomolecule design and discovery, the Modigy workflow (Figure 1) expands its horizons by enabling extensive exploration of the sequence space of biomolecular binding pairs [33,34], and holds transformative potential for computational biomolecule discovery and design (Figure 2).

3.1. Design of Semaglutide Analogues with Enhanced Binding Affinity to GLP-1R

Semaglutide, a GLP-1 receptor agonist, is effective in treating type 2 diabetes mellitus by aiding in blood sugar regulation and weight reduction [35,36,37]. In 2021, a Val27-Arg28 substitution was manually designed and introduced into the semaglutide backbone, resulting in an increase in the ligand-receptor Kd [29,38,39]. Afterwards, using the Modigy workflow (Figure 1), 8915 semaglutide analogues were computationally designed with a comprehensive structural biophysics-based strategy [34,40]. Among these, one analogue stood out with a Kd to GLP-1R over 113 times higher than that of native semaglutide, with a Kd of 3.0 × 10-8 M compared to 3.4 × 10-6 M for native semaglutide [34,40]. This study highlights the potential of this Modigy-based approach in designing semaglutide analogues with improved GLP-1R binding affinity and efficacy in diabetes treatment and weight management [41,42,43,44].

3.2. Scalable Antigen-Antibody Binding Affinity Landscape: A Case Study with ENHERTU

Optimizing binding affinities for antibody-drug conjugates (ADCs) is critical for their therapeutic efficacy and specificity. Most ADCs are engineered to achieve equilibrium Kd in the range of 0.1 to 1 nM, but there is a paucity of published data delineating the optimal binding affinity range for improved therapeutic outcomes [45,46]. Trastuzumab deruxtecan (ENHERTU®) is a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate developed for treating HER2-expressing solid tumors [47,48,49]. Trastuzumab, the monoclonal antibody in ENHERTU®, binds to the extracellular domain of the HER2 receptor, inhibiting downstream signaling pathways and mediating antibody-dependent cellular cytotoxicity [32,50].
Using ENHERTU® as an example, a recent computational study [31] reported a scalable antigen-antibody binding affinity landscape using the Modigy workflow [25]. Of particular interest is the HER2-Trastuzumab-Pertuzumab binding affinity landscape as a function of site-specific missense mutations, such as this particular S911F mutation in chain C of Pertuzumab. With the Prodigy server [23,24], the impact of this mutation is reassessed, leading to an antigen-antibody Kd of 2.9 × 10-10 M for the Her2-Pertuzumab interaction, compared to 1.9 × 10-8 M for the native experimental Her2-Trastuzumab-Pertuzumab complex (PDB entry 6OGE [32]). This increase in the antigen-antibody binding affinity due to the S911F substitution underscores the potential of the Modigy workflow [25] for both ADC efficacy optimization [45,46] and monoclonal antibody affinity maturation [51,52].

4. How Does the Modigy Workflow Contribute to Biomolecular AIDD?

The past century, along with the beginning of this one, saw a transformative era in drug discovery and design with the advent of computer-aided drug discovery and design (CADD) and AI-enabled drug discovery and design (AIDD), supported by the development of extensive chemical and biological databases [11,15,22,53,54,55] and machine learning algorithms [56]. For instance, recent advancements in this field have profoundly impacted structural biology (e.g., protein structure prediction by AlphaFold [54]) and drug discovery and design [57,58]. Yet, the predictions made by CADD tools are only as good as the data they are trained on, i.e., if the data are insufficient or of poor quality, the predictions are likely to be inaccurate and thus unreliable.
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Figure 3. A synthetic data and AIDD perspective of the Modigy workflow (Figure 1). In this figure, expt data represents experimentally measured inter-molecular Kd data, while synt data represents drug-target Kd generated by Modigy workflow (Figure 1).
Figure 3. A synthetic data and AIDD perspective of the Modigy workflow (Figure 1). In this figure, expt data represents experimentally measured inter-molecular Kd data, while synt data represents drug-target Kd generated by Modigy workflow (Figure 1).
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Thus, the Modigy (Figure 1) workflow here addresses the critical bottleneck of limited experimental data by generating synthetic data, which constitutes a paradigm shift (Figure 4) from linear accumulation of experimental Kd data to exponential accumulation of computational Kd data with reasonable accuracy. This paradigm shift facilitates the integration of AI algorithms in biomolecule discovery and design, improving the training of AI models and enhancing their predictive capabilities [59], as combining synthetic data with experimental data [11,15] in hybrid models can enhance the overall accuracy and robustness of predictions by AIDD tools. While the Modigy workflow improves the training and performance of AI models, paves the way for more sophisticated and effective AI-driven drug discovery approaches, it also encourages the development of new AI algorithms tailored to leverage synthetic data, fostering continued innovation and advancement in the field.
Additionally, the Modigy workflow (Figure 1) is inherently scalable and applicable for existing experimental databases like PDB [22], allowing for high-throughput creation of astronomical datasets of synthetic inter-molecular Kd data [25]. Take semaglutide for instance, to introduce three site-specific missense mutations into the semaglutide backbone requires a total of 26,208,000 homology structural models with reasonable accuracy [41] to be built using Modeller [21] and a total of 26,208,000 Prodigy-based [23,24] calculations of the binding affinities between semaglutide analogues and GLP-1R. For Molecule X (a random protein consisting of 100 amino acids), the number soars from 26,208,000 to 1,293,600,000 (Table 1). In practice, an exhaustive exploration of the entire biomolecular space [60,61] is both impossible and unnecessary, which is where AI algorithms come in for continued development of computational biomolecule design and discovery. Moreover, this article proposes an open strategy [62] to making it conceivable to generate astronomical amounts of Kd data, with which to build AIDD models with reasonable accuracy and efficiency [63], as openness in both experimental data acquisition and synthetic data generation, and in AI algorithm development, is essential for promoting transparency, reproducibility, and collaboration within the drug discovery and design community [2,63].

5. Limitations of the Modigy Workflow in Drug Design and Discovery

While the proposed Modigy workflow (Figure 1) holds potential for biomolecular CADD and AIDD, it is essential to recognize its limitations and identify areas for future research and development. The Modigy approach (Figure 1) does not work in the absence of accurate structural information and is tailored specifically for biomolecules, making it unsuitable for small molecule discovery and design. Although Prodigy [23,24] does account for temperature in Kd calculation, the Modigy approach (Figure 1) does not consider other parameters such as pH [64,65], site-specific protonation states (e.g., protein side chain pKa) [66,67], post-translational modifications [68,69], post-expression modifications [29,30] and buffer conditions [70]. Furthermore, the Modigy approach (Figure 1) is not applicable for the inclusion of unnatural amino acids into biomolecules [56,71] and is limited to biomolecules, excluding other molecular types and drug modalities [60,61].

6. Conclusion

The Modigy workflow (Figure 1) transforms the landscape of computational biomolecule design and discovery by generating high-quality synthetic structural and intermolecular Kd data. By addressing the limitations of existing experimental datasets [11,15] and integrating advanced computational techniques with AI algorithms, this Modigy workflow (Figure 1) provides a technically feasible approach for accelerating the development of therapeutic biomolecular candidates with improved efficacy and specificity, as it is able to not only improves the accuracy and efficiency of computational models, but also contributes to future advancements in biomolecule discovery and design enabled by both AI algorithms and structural biophysics [2,7].

7. Ethical Statement

No ethical approval is required.

8. Declaration of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this work, the author used OpenAI’s ChatGPT in order to improve the readability of the manuscript, and to make it as concise and short as possible. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Author Contributions

Conceptualization, W.L.; methodology, W.L.; software, W.L.; validation, W.L.; formal analysis, W.L.; investigation, W.L.; resources, W.L.; data duration, W.L.; writing–original draft preparation, W.L.; writing–review and editing, W.L.; visualization, W.L.; supervision, W.L.; project administration, W.L.; funding acquisition, not applicable.

Funding

This research received no external funding.

Conflicts of Interest

The author declares no conflict of interest.

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Figure 1. A detailed flowchart of automated in silico generation of synthetic structural and Kd data. In this figure, Modigy represents an abbreviated name of the workflow consisting of Modeller [21] and Prodigy [23,24].
Figure 1. A detailed flowchart of automated in silico generation of synthetic structural and Kd data. In this figure, Modigy represents an abbreviated name of the workflow consisting of Modeller [21] and Prodigy [23,24].
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Figure 2. A synthetic data and CADD perspective of the Modigy (Figure 1) workflow. In this figure, expt data represents experimentally measured drug-target Kd, while synt data represents drug-target Kd generated by Modigy workflow (Figure 1).
Figure 2. A synthetic data and CADD perspective of the Modigy (Figure 1) workflow. In this figure, expt data represents experimentally measured drug-target Kd, while synt data represents drug-target Kd generated by Modigy workflow (Figure 1).
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Figure 4. Inter-molecular binding affinity synthetic data augmentation expands the horizon of computational biomolecule design and discovery. In this three-tier sketch of the sequence space of biomolecular binding pairs, the Modigy workflow (Figure 1) bridges the gap between experimentally measured Kd data and its uncharted territory.
Figure 4. Inter-molecular binding affinity synthetic data augmentation expands the horizon of computational biomolecule design and discovery. In this three-tier sketch of the sequence space of biomolecular binding pairs, the Modigy workflow (Figure 1) bridges the gap between experimentally measured Kd data and its uncharted territory.
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Table 1. The size ( s = g ( k , n ) = k ! n ! ( k − n ) ! × 20 n ) [25] of the synthetic structural data set based on the semaglutide-GLP-1R complex structure. Here, k represents the length of the semaglutide backbone, and n represents the number of missense mutations introduced into the semaglutide backbone, with the value of n / k being key to ensuring the overall reasonable accuracy of the synthetic data of inter-molecular binding affinities.
Table 1. The size ( s = g ( k , n ) = k ! n ! ( k − n ) ! × 20 n ) [25] of the synthetic structural data set based on the semaglutide-GLP-1R complex structure. Here, k represents the length of the semaglutide backbone, and n represents the number of missense mutations introduced into the semaglutide backbone, with the value of n / k being key to ensuring the overall reasonable accuracy of the synthetic data of inter-molecular binding affinities.
6|cSize (s) of the synthetic structural and biophysical data set
Semaglutide backbone (28 Aa) Molecule X (100 Aa)
g(28,1) 28 ! 1 ! ( 27 ) ! × 20 1 560 g(100,1) 100 ! 1 ! ( 99 ) ! × 20 1 2000
g(28,2) 28 ! 2 ! ( 26 ) ! × 20 2 151200 g(100,2) 100 ! 2 ! ( 98 ) ! × 20 2 1980000
g(28,3) 28 ! 3 ! ( 25 ) ! × 20 3 26208000 g(100,3) 100 ! 3 ! ( 97 ) ! × 20 3 1293600000
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