Abstract
A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models.
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Abbreviations
- ABM:
-
Agent-based model
- AMD:
-
AMD3100
- BMSC:
-
Bone marrow stromal cell
- BSV:
-
Between-subject variability
- BZM:
-
Bortezomib
- CAD:
-
Computer-aided design
- CG:
-
Coarse-grained
- CXCR4:
-
C-X-C chemokine receptor type 4
- DPD:
-
Dissipative particle dynamics
- ECM:
-
Extracellular matrix
- EPR:
-
Enhanced permeability and retention
- HPV:
-
Human papillomavirus
- IFP:
-
Interstitial fluid pressure
- MC:
-
Monte Carlo
- MCMC:
-
Markov chain Monte Carlo
- MD:
-
Molecular dynamics
- MF:
-
Multiscale factorization
- MIC:
-
Myeloma initiating cell
- MM:
-
Multiple myeloma
- NC:
-
Nanocarrier
- NP:
-
Nanoparticle
- NS:
-
Navier–Stokes
- PBPK:
-
Physiologically-based pharmacokinetic
- PC:
-
Cancer progenitor cell
- PDB:
-
Protein Data Bank
- QM/MM:
-
Quantum mechanics/molecular mechanics
- RUV:
-
Residual unknown variability
- SCB:
-
Systems chemical biology
- SDF1:
-
Stromal cell-derived factor 1
- TMM:
-
Terminal multiple myeloma cell
- WHAM:
-
Weighted histogram analysis method
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Acknowledgments
This work was supported in part by NIH grants R01CA138264 (ASP), U01HL126273 (CEC), U01EB016027 (DME), R01EB006818 (DME), R01-GM-115839 and P30-DK-42086 (GA), R01GM077138 (JPS) and R15EB015105 (YL) as well as EPA grant R835001 (JPS). WRC was funded under the Laboratory Directed Research Program at the Pacific Northwest National Laboratory. PNNL is operated by Battelle for the U.S. Department of Energy under Contract DE-AC06-76RLO.
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Clancy, C.E., An, G., Cannon, W.R. et al. Multiscale Modeling in the Clinic: Drug Design and Development. Ann Biomed Eng 44, 2591–2610 (2016). https://doi.org/10.1007/s10439-016-1563-0
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DOI: https://doi.org/10.1007/s10439-016-1563-0