title: Molecular mechanism matters: Benefits of mechanistic computational models for drug development.
abstract: Making drug development a more efficient and cost-effective process will have a transformative effect on human health. A key, yet underutilized, tool to aid in this transformation is mechanistic computational modeling. By incorporating decades of hard-won prior knowledge of molecular interactions, cellular signaling, and cellular behavior, mechanistic models can achieve a level of predictiveness that is not feasible using solely empirical characterization of drug pharmacodynamics. These models can integrate diverse types of data from cell culture and animal experiments, including high-throughput systems biology experiments, and translate the results into the context of human disease. This provides a framework for identification of new drug targets, measurable biomarkers for drug action in target tissues, and patient populations for which a drug is likely to be effective or ineffective. Additionally, mechanistic models are valuable in virtual screening of new therapeutic strategies, such as gene or cell therapy and tissue regeneration, identifying the key requirements for these approaches to succeed in a heterogeneous patient population. These capabilities, which are distinct from and complementary to those of existing drug development strategies, demonstrate the opportunity to improve success rates in the drug development pipeline through the use of mechanistic computational models.
authors.affiliation: Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States. Electronic address: lwendel2@jhmi.edu.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Clegg
authors.affiliation: Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, United States.
authors.forename: Feilim
authors.initials: F
authors.lastname: Mac Gabhann
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007511:Ischemia / Q000188:drug therapy; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy; D057170:Translational Research, Biomedical; D014584:User-Computer Interface
keywords: Drug development; Mechanistic computational model; Pharmacodynamics; Pharmacokinetics; Systems pharmacology