Computational modeling, cell biological, biophysical, chemical experimentation, and animal models will be combined in a novel approach to prescreening of compounds for drug design, which is rendered to be more efficient and rapid than current approaches. This interdisciplinary study integrates: (i) computational modeling incorporating protein dynamics to screen for compounds that favor a particular protein conformation and with that best induce cell death, followed by refinement to predict more efficient compounds;(ii) chemical synthesis of the most promising compounds;(iii) cell biological experimentation to verify predictions, aid in the refinement of the computational predictions and perform preclinical evaluations;followed by (iv) screening of the most promising compounds in vivo. We are targeting a specific protein, the MMR protein MSH2 (MutS homolog 2), since we have shown that this protein undergoes specific conformational changes in response to DNA damage, specifically due to platinum damage, which ultimately results in the induction of cell death. We are specifically designing compounds that will induce the same conformational changes in MSH2 and ultimately trigger cell-death. Our multi-disciplinary approach has multiple novel aspects. First, we are using a novel combination of computational modeling and cell biology as an efficient way of prescreening promising anticancer drugs. Second, in targeting the MSH2-dependent apoptotic pathway, we are targeting an important cellular pathway whose existence and importance has only recently come to light. Third, we are targeting specific """"""""death"""""""" conformations of MSH2, discovered computationally, to eliminate the majority of compounds in the first step of the screen and induce a specific cell death pathway. With this approach, the compounds will be designed to activate a naturally occurring pathway, as opposed to inhibiting a pathway. Fourth, this project closely integrates computational modeling of the molecular details of the response to damage by chemotherapeutics with biological experimentation. PUBLIC HEALTH REVELANCE:The eventual goal of this research is the discovery and design of improved chemotherapeutics, ones that are both safer and more effective, based on a MSH2-dependent apoptotic pathway.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Arts and Sciences
United States
Zip Code
Godwin, Ryan; Gmeiner, William; Salsbury Jr, Freddie R (2016) Importance of long-time simulations for rare event sampling in zinc finger proteins. J Biomol Struct Dyn 34:125-34
Lu, Yan; Salsbury Jr, Freddie R (2015) Autoinhibitory mechanisms of ERG studied by molecular dynamics simulations. AIP Adv 5:017130
Lu, Yan; Salsbury, Freddie R (2015) Recapturing the Correlated Motions of Protein Using Coarse- Grained Models. Protein Pept Lett 22:654-9
Negureanu, Lacramioara; Salsbury Jr, Freddie R (2014) Non-specificity and synergy at the binding site of the carboplatin-induced DNA adduct via molecular dynamics simulations of the MutS*-DNA recognition complex. J Biomol Struct Dyn 32:969-92
Negureanu, Lacramioara; Salsbury Jr, Freddie R (2013) Destabilization of the MutSα's protein-protein interface due to binding to the DNA adduct induced by anticancer agent carboplatin via molecular dynamics simulations. J Mol Model 19:4969-89
Ghosh, Supratim; Salsbury Jr, Freddie R; Horita, David A et al. (2013) Cooperative stabilization of Zn(2+):DNA complexes through netropsin binding in the minor groove of FdU-substituted DNA. J Biomol Struct Dyn 31:1301-10
AbdelHafez, ElShimaa M N; Diamanduros, Andrew; Negureanu, Lacramioara et al. (2013) Computational and synthetic studies towards improving rescinnamine as an inducer of MSH2-dependent apoptosis in cancer treatment. Mol Cancer Biol 1:
Negureanu, Lacramioara; Salsbury, Freddie R (2012) Insights into protein - DNA interactions, stability and allosteric communications: a computational study of mutS*-DNA recognition complexes. J Biomol Struct Dyn 29:757-76
Negureanu, Lacramioara; Salsbury Jr, Freddie R (2012) The molecular origin of the MMR-dependent apoptosis pathway from dynamics analysis of MutSα-DNA complexes. J Biomol Struct Dyn 30:347-61
Salsbury Jr, Freddie R; Yuan, Ye; Knaggs, Michael H et al. (2012) Structural and electrostatic asymmetry at the active site in typical and atypical peroxiredoxin dimers. J Phys Chem B 116:6832-43

Showing the most recent 10 out of 16 publications