David L Mobley

Associate Professor
Pharmaceutical Sciences

Associate Professor, Chemistry
School of Physical Sciences

B.S., University of California, Davis, 2000, Physics

M.S., University of California, Davis, 2002, Physics

Ph.D., University of California, Davis, 2004, Physics

Phone: 949-385-2436
Fax: 949-824-2929
Email: dmobley@uci.edu

University of California, Irvine
3134B Natural Sciences 1
Mail Code: 3958
Irvine, CA 92697

picture of David L Mobley

Computational techniques for drug discovery, free energy calculations, molecular simulations, solubility
URLs Group Website
Google Scholar Profile
Hewlett-Packard Outstanding Junior Faculty Award, American Chemical Society, 2009
National Science Foundation CAREER Award, 2014
Appointments 2004-2008: Postdoctoral Researcher in Pharmaceutical Chemistry at the University of California, San Francisco, with Ken Dill.
Our research focuses on applying computational and theoretical methods to understand and quantitatively predict fundamental biological processes such as protein-ligand binding, solvation, and solubility. We seek to provide an atomically detailed understanding of these processes at a level of accuracy that can be useful in industrial applications.

One major emphasis is binding prediction. A major focus is the binding of small-molecule ligands to proteins. While current computational methods see widespread use in the pharmaceutical industry in drug discovery applications, accuracy is limited and these approaches fall far short of the goal of using computers to suggest new drug candidates. Methods we recently developed and applied have achieved far greater accuracies at computing and even predicting binding affinities than previous methods, so we are working to begin applying these in more complicated and pharmaceutically relevant binding sites. Projects involve both applications to drug discovery problems, and methodological improvements. Our work in this area focuses on using so-called alchemical free energy techniques for predicting binding affinities using molecular simulations.

We have several more application-oriented problems of binding free energy techniques, and are also looking for new collaborations. In one of these projects, we are working in collaboration with experimentalists to guide discovery/development of new antibacterials targeting gram positive bacteria. The project here takes two tracks. One begins with an existing inhibitor of our target enzyme in E. Coli and modifies it to design around binding site changes in gram positive bacteria, screening potential new inhibitors with free energy techniques before synthesizing them. Another track uses virtual screening, docking, and finally free energy calculations to screen a large library of potential inhibitors and identify promising compounds for experimental testing. In another project, we are collaborating with a pharmaceutical company, using free energy calculations to help understand affinity trends in an existing lead series for another antibacterial target.

For more information, see the lab website at http://mobleylab.org.
Publications See Google Scholar Profile and Lab Website for updated lists of publiations
  Y-C. Zheng, Y-C. Duan, J.-L. Ma, R.-M. Xu, X. Zi, W.-L. Lv, M.-M. Wang, X.-W. Ye, S. Zhu, D. L. Mobley, Y. Zhu, J.-W. Wang, J.-F. Li, Z.-R. Wang, W. Zhao, H.-M. Zhao, “Triazole-dithiocarbamate based, selective LSD1 inactivators inhibit gastric cancer cell growth, invasion, and migration,” J. Med. Chem. 56(21):8543-8560 (2013).
  G. J. Rocklin, D. L. Mobley, K. A. Dill, and P. H. Hünenberger*, “Calculating the binding free energies of charged species based on explicit-solvent simulations employing lattice-sum methods: An accurate correction scheme for finite-size effects”, J. Chem. Phys. 139(18):184103 (2013).
  S. Liu, Y. Wu, T. Lin, R. Abel, J. Redmann, C. M. Summa, V. R. Jaber, N. M. Lim, and D. L. Mobley, “Lead Optimization Mapper: Automating free energy calculations for lead optimization”, J. Comput. Aided Mol. Design 27(9):755-770 (2013).
  G. J. Rocklin, S. E. Boyce, M. Fisher, I. Fish, D. L. Mobley, B. K. Shoichet, and K. A. Dill. “Blind prediction of charged ligand binding affinities in a model binding site”, J. Mol. Biol. 425(22):4569-4583 (2013).
  G. J. Rocklin, D. L. Mobley, and K. A. Dill, “Calculating the sensitivity and robustness of binding free energy calculations to force field parameters”, J. Chem. Theory Comput. 9: 3072-3083 (2013).
  A. Thaxton, S. Izenwasser, D. Wade, E. D. Stevens, D. L. Mobley, V. Jaber, S. A. Lomenzo, M. L. Trudell, “3-aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters,” Bioorg. Med. Chem. Lett. 23: 4404-4407 (2013).
  J. D. Chodera and D. L. Mobley, “Entropy-enthalpy compensation: Role and ramifications in biomolecular ligand recognition and design”, Annual Reviews in Biophysics 42:121-142 (2013).
  G. J. Rocklin, D. L. Mobley, and K. A. Dill, "Separated topologies - A method for relative binding free energy calculations using orientational restraints", in J. Chem. Phys. 138:085104 (2013).
  M. R. Shirts and D. L. Mobley, "An introduction to best practices in free energy calculations", in Biomolecular Simulations: Methods and Protocols, Methods in Molecular Biology 924:271-311 (2013).
  D. L. Mobley and P. V. Klimovich, "Perspective: Alchemical free energy calculations for drug discovery", Journal of Chemical Physics, 137:230901 (2012)
  D. L. Mobley, S. Liu, D. Cerutti, W. C. Swope, and J. Rice, “Alchemical prediction of hydration free energies for SAMPL”, special issue, J. Comput. Aided Mol. Design 26(5):551-562 (2012).
  C. D. Savoie and D. L. Mobley*, “Understanding the structural and functional effects of mutations in HIV-1 protease mutants using 100 ns molecular dynamics simulations”, Journal of Computational Science Education 2(1): 28-34 (2011).
  D. L. Mobley, “Let’s get honest about sampling”, invited perspective, J. Comput. Aided Mol. Design Design 26(1):93-95 (2012).
  A. S. Paluch, D. L. Mobley, and E. J. Maginn*, “Small Molecule Solvation Free Energy: Enhanced Conformational Sampling Using Expanded Ensemble Molecular Dynamics Simulation”, Journal of Chemical Theory and Computation 7:2910-2918 (2011).
  D. L. Mobley and M. R. Shirts*, “An introduction to best practices in free energy calculations”, in “Biomolecular Simulations: Methods and Protocols”, Methods in Molecular Biology.
  J. D. Chodera*, D. L. Mobley, M. R. Shirts, R. W. Dixon, K. Branson, V. S. Pande, “Alchemical free energy methods for drug discovery: Progress and challenges,” Current Opinion in Structural Biology 21:150-160 (2011).
  X. Gu, S. Izenwasser, D. Wade, A. Housman, G. Gulasey, J. B. Rhoden, C. D. Savoie, D. L. Mobley, S. A. Lomenzo, and M. D. Trudell*. “Synthesis and Structure-Activity Studies of Benzyl Ester Meperidine and Normeperidine Derivatives as Selective Serotonin Transporter Ligands”, Bioorg. Med. Chem. Lett. 18: 8356-8364, 2010.
  P. V. Klimovich and D. L. Mobley*, “Predicting hydration free energies using all-atom molecular dynamics simulations and multiple starting conformations”, J. Computer-Aided Molecular Design 24: 307-316 (2010).
  M. R. Shirts*, D. L. Mobley and S. P. Brown, “Free energy calculations in structure-based drug design”, in “Structure Based Drug Design”, Cambridge University Press (2010), edited by Kenneth M. Merz, Dagmar Ringe and Charles H. Reynolds. Invited chapter.
  J. Ponder*, C. Wu, V. Pande, J. Chodera, M. Schneiders, D. Mobley, I. Haque, D. Lambrecht, R. Distasio, Jr., M. Head-Gordon, G. Clark, M. Johnson, T. Head-Gordon. “Current status of the AMOEBA polarizable force field”, J. Phys. Chem. B. 114: 2549-2564 (2010). (Cover article).
  H. Kaur, S. Izenwasser, A. Verma, D. Wade, A. Housman, E. D. Stevens, D. L. Mobley, and M. L. Trudell*. “Synthesis and monoamine transporter affinity of 3?-Arylmethoxy-3?-arylnortropanes”, Bioorg. Med. Chem. Lett. 10:6865-6868 (2009).
  S. E. Boyce#, D. L. Mobley#, G. Rocklin, A. P. Graves, K. A. Dill, B. K. Shoichet. “Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site”, J. Mol. Biol. 394: 747-763 (2009).
  C. L. McClendon, G. Friedman, D. L. Mobley, H. Amirkhani, and M. P. Jacobson*, “Quantifying correlations between allosteric sites in thermodynamic ensembles”, J. Chem. Theory Comput. 5 (9): 2486-2502 (2009).
  D. L. Mobley* and K. A. Dill, “The binding of small-molecule ligands to proteins: ‘What you see’ is not always ‘what you get’”, Structure 17(4): 489-498 (2009).
  D. L. Mobley*, C. I. Bayly, M. D. Cooper, and K. A. Dill, “Predictions of hydration free energies from all-atom molecular dynamics simulations”, J. Phys. Chem. B 113: 4533-4537 (2009). Invited article, special issue on “Calculation of Aqueous Solvation Energies of Drug-Like Molecules: A Blind Challenge”.
  D. L. Mobley*, C. I. Bayly, M. D. Cooper, M. R. Shirts, and K. A. Dill. “Small molecule hydration free energies in explicit solvent: An extensive test of fixed-charge force fields”, J. Chem. Theory Comput. 5: 350-358 (2009)
  D. L. Mobley, A. Barber II, C. Fennell, and K. A. Dill*, “Charge asymmetries in hydration of polar solutes”, J. Phys. Chem. B. 112: 2405-2414 (2008). Erratum: D. L. Mobley*, J. R. Baker, A. E. Barber II, C. J. Fennell, and K. A. Dill, “Erratum: Charge Asymmetries in Hydration of Polar Solutes”, J. Phys. Chem. B (2011)
  D. L. Mobley*, J. D. Chodera and K. A. Dill, “Entropy and conformational change in implicit solvent simulations of small molecules”, J. Phys. Chem. B, 112: 938-946 (2008).
  A. Nicholls*#, D. L. Mobley*#, J. P. Guthrie, J. D. Chodera, and V. S. Pande. “Predicting small-molecule solvation free energies: A blind challenge test for computational chemistry,” J. Med. Chem. 51:769-779 (2008).
  T. Steinbrecher, D. L. Mobley, and D. A. Case*. “Non-linear scaling schemes for Lennard-Jones interactions in free energy calculations”, J. Chem. Phys., 127: 214108 (2007). Selected for the Virtual Journal of Biological Physics 14 (12) (2007).
  M. R. Shirts#*, D. L. Mobley#, J. D. Chodera, and V. S. Pande. “Accurate and efficient corrections for missing dispersion interactions in molecular simulations”, J. Phys. Chem. B. 111:13052-13063 (2007).
  M. R. Shirts#*, D. L. Mobley#, J. D. Chodera, and V. S. Pande. “Accurate and efficient corrections for missing dispersion interactions in molecular simulations”, J. Phys. Chem. B. 111:13052-13063 (2007).
  D. L. Mobley#, A. P. Graves#, J. D. Chodera, A. C. McReynolds, B. K. Shoichet* and K. A. Dill*, “Predicting absolute ligand binding free energies to a simple model site,” Journal of Molecular Biology 371(4): 1118-1134 (2007).
  M. R. Shirts*, D. L. Mobley, and J. D. Chodera, “Alchemical free energy calculations: Ready for prime time?” Annual Reports in Computational Chemistry 3: 41-59 (2007), invited review.
  D. L. Mobley, J. D. Chodera, and K. A. Dill*, “Confine and Release Method: Obtaining Correct Binding Free Energies in the Presence of Protein Conformational Change”, Journal of Chemical Theory and Computation 3(4): 1231 (2007).
  D. L. Mobley, E. Dumont, J. D. Chodera, K. A. Dill*, “Comparison of charge models for fixed-charge force fields: Small-molecule hydration free energies in explicit solvent”, J. Phys. Chem. B 111(9):2242 (2007). Erratum: DOI 10.1021/jp108173f (2011).
  A. M. Stein, T. Demuth, D. Mobley, M. Berens, and L. Sander*, “A Mathematical Model of Glioblastoma Tumor Spheroid Invasion in a 3-D in vitro Experiment”, Biophysical Journal, 92(1):356 (2007).
  D. L. Mobley, J. D. Chodera, K. A. Dill*, “On the use of orientational restraints and symmetry number corrections in alchemical free energy calculations”, J. Chem. Phys. 125:084902 (2006). Selected for the Virtual Journal of Biological Physics Research 12(5) (2006).
  D. L. Mobley, C. R. Pike, J. E. Davies, D. L. Cox*, R. R. P. Singh, "Hysteresis loops of Co-Pt perpendicular magnetic multilayers". Journal of Physics: Condensed Matter, 16: 5897-5906 (2004).
  D. L. Mobley, D. L. Cox, R. R. P. Singh, M. W. Maddox, M. L. Longo, "Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers". Biophysical Journal, 86(6): 3585-3597 (2004).
  D. L. Mobley, D. L. Cox*, R. R. P. Singh, R. V. Kulkarni and A. Slepoy, "Simulations of Oligomeric Intermediates in Prion Diseases", Biophysical Journal, 85(4):2213-2223 (2003).
Grant We appreciate funding from the NIH and NSF. Please see our website at mobleylab.org for details.
American Chemical Society
Biophysical Society
Other Experience Postdoctoral Researcher
University of California, San Francisco 2004—2008

Chief Science Officer
Simprota Corporation 2008—2008

Assistant Professor, Chemistry
University of New Orleans 2008—2012

Adjunct Professor, Chemistry
University of New Orleans 2012—pres

Scientific Advisory Board
Schrödinger Software 2013—pres

Graduate Programs Pharmacological Sciences


Link to this profile http://www.faculty.uci.edu/profile.cfm?faculty_id=5908
Last updated 05/30/2016