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.
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|Negureanu, Lacramioara; Salsbury Jr, Freddie R (2013) Destabilization of the MutS*'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|
|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|
|Yuan, Ye; Knaggs, Michael H; Poole, Leslie B et al. (2010) Conformational and oligomeric effects on the cysteine pK(a) of tryparedoxin peroxidase. J Biomol Struct Dyn 28:51-70|
|Salsbury Jr, F R (2010) Effects of Cisplatin binding to DNA on the dynamics of the E. Coli MutS dimer. Protein Pept Lett 17:744-50|
|Salsbury Jr, Freddie R (2010) Molecular dynamics simulations of protein dynamics and their relevance to drug discovery. Curr Opin Pharmacol 10:738-44|