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Multiple Ligand Simultaneous Docking (MLSD) and Its Applications to Fragment Based Drug Design and Drug Repositioning

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2012, Doctor of Philosophy, Ohio State University, Biophysics.

This thesis presents a novel multiple ligand simultaneous docking (MLSD) method for simulating protein-ligand molecular recognition and a novel protocol for fragment-based drug design by combining MLSD and drug repositioning. Different cancer molecular targets, namely GP130 and STAT3, in IL-6/GP130/STAT3 signaling pathway were used as use cases for the proposed MLSD and drug design protocol.

Conventional docking methods simulate only one single ligand at a time during docking process. In reality, molecular recognition process always involves multiple molecular species. The first part of this research developed a MLSD simulation method which can simulate the orchestrated action of multiple ligands binding to the active site of protein. The methodology proves robust through systematic testing against several diverse model systems: E. coli PNP complex with two substrates, SHP2NSH2 complex with two peptides and cancer target Bcl-xL in complex with ABT-737 fragments. In ABT-737 and SHP2NSH2 cases, conventional single ligand docking failed to find correct binding modes due to energetic and dynamic coupling among ligands, whereas MLSD resulted in the correct binding modes. In PNP case, the MLSD simulations captured the binding dynamics, which is consistent with proposed enzymatic mechanism from the experiment. The work also compared two search strategies: Lamarckian Genetic Algorithm (LGA) and Particle Swarm Optimization (PSO), which had respective advantages depending on the specific systems.

Molecular docking finds its major applications in drug design and discovery. Conventional high throughput screening (HTS) drug discovery approach identifies many hits, but few of them can be developed into drugs. The second part of this research applied MLSD to fragment-based drug design and proposed a novel drug discovery protocol by combining MLSD and drug repositioning. It proceeds as follows. 1. A small library of drug scaffolds is identified for the binding hot spots of target protein. 2. Selected drug fragments are simultaneously docked to protein binding sites by MLSD, like fitting the right piece into the right place in jigsaw puzzle, and tethered properly to generate virtual drug templates. 3. Structure or chemical feature similarity search of template compounds on drug databases can potentially reposition existing drugs to new targets. Cancer targets GP130 and STAT3 were used as two test cases. In the case of STAT3, drug scaffolds were simultaneously docked into hot spots of STAT3 SH2 domain by MLSD, followed by tethering to generate virtual template compounds. Similarity searching of virtual compounds in DrugBank identified Celecoxib as a novel inhibitor of STAT3. A few novel compounds were designed from virtual templates, which demonstrated more potent inhibition of STAT3. In the case of target GP130, our approach quickly identified drug Raloxifene and Bazedoxifene, as novel inhibitors to disrupt IL-6/GP130 protein-protein interactions through targeting GP130 D1 domain, which were confirmed by multiple cancer cell assays.

The MLSD and the drug discovery protocol presented hold exciting potential for modeling molecular recognition and fragment based drug design for other therapeutic targets.

Chenglong Li (Advisor)
Kun Huang (Committee Member)
Michael Poirier (Committee Member)
Guo-Liang Wang (Committee Member)
143 p.

Recommended Citations

Citations

  • Li, H. (2012). Multiple Ligand Simultaneous Docking (MLSD) and Its Applications to Fragment Based Drug Design and Drug Repositioning [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1324606149

    APA Style (7th edition)

  • Li, Huameng. Multiple Ligand Simultaneous Docking (MLSD) and Its Applications to Fragment Based Drug Design and Drug Repositioning. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1324606149.

    MLA Style (8th edition)

  • Li, Huameng. "Multiple Ligand Simultaneous Docking (MLSD) and Its Applications to Fragment Based Drug Design and Drug Repositioning." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1324606149

    Chicago Manual of Style (17th edition)