Multiscale Modeling in the Clinic: Drug Design and Development

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 (i) excitable systems and applications in cardiac disease; (ii) stem cell driven complex biosystems; (iii) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (iv) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (v) 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.

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

“…Central to the success of modelling and simulation approaches for predictive safety pharmacology is the development of models that are informed and validated via tightly planned integration of experiments and simulations at every stage (Clancy et al . ). It will be critical to demonstrate the usefulness of the frameworks and to validate their utility and reproducibility.…”

Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation

“…; Clancy et al . ). We conclude that while many challenges and limitations in the field still exist, atomistic simulations of ion channels are entering a golden era of theoretical understanding and biomedical application, and although controversial findings and differing viewpoints will likely linger, such discourse is indispensable for moving the field forward.…”

“…In particular, significant advancement is likely to be made in computing kinetic information for physiological processes that cannot easily be determined experimentally, such as ion channel gating, and state-specific drug binding (entry) and unbinding (egress) rates. This type of simulation-derived data can potentially be used to generate parameters for many of the function-scale models used in predictive physiology, pathophysiology and pharmacology (Silva et al 2009;Yarov-Yarovoy et al 2014;Clancy et al 2016). We conclude that while many challenges and limitations in the field still exist, atomistic simulations of ion channels are entering a golden era of theoretical understanding and biomedical application, and although controversial findings and differing viewpoints will likely linger, such discourse is indispensable for moving the field forward.…”

Targeting Phospholipid Metabolism in Cancer

“…Such types of analyses have already been performed for drug design and development (193) and recently for tissue-specific metabolic networks, including tumors (194). …”