• Designing Specific Inhibitors to Target S100B in Melanoma

      Vera-Rodriguez, Darex J.; Young, Brianna; Spriggs, Shardell; Yu, Wenbo; Wilder, Paul T.; MacKerell, Alexander D., Jr.; Weber, David J., Ph.D. (2020)
      Malignant melanoma (MM) is defined as the most dangerous form of skin cancer, causing a large majority of skin cancer deaths. Previous studies demonstrate S100B as a tumor marker in MM, a protein that interacts with the tumor suppressor p53, inhibiting p53 function. With the goal of blocking this interaction, three binding sites on S100B for small molecules have been identified. However, developing drugs specific for S100B over other S100-family members remains a challenge. This project aims to identify S100B-specific small molecule inhibitors and understand the basis of their specificity over other S100 family members, specifically S100A1. A 2D-[1H,15N] NMR HSQC of S100B bound to a non-specific fragment showed multiple chemical shifts perturbations (CSPs) including residues A9, L10, F43, L40, F73, and C84. Interestingly, fewer and less pronounced CSPs were observed for a S100B-specific fragment. Site-Identified Ligand Competitive Saturation (SILCS) molecular dynamics (MD) simulations were performed to determine potential S100B binding sites that could explain the CSPs. Results show a strong hydrophobic pocket at low Grid Free Energy (GFE) levels comprised by the residues that showed CSPs for compounds that bind S100B. FDA-approved compounds were tested using SILCS-Monte Carlo (MC) to determine ligand binding poses at this pocket. Specific compounds were targeted with strong hydrophobic interactions and hydrogen bonds at low Ligand GFE (GFE). These data provide important information relevant to developing S100B-specific drugs to treat MM.
    • Development of the Drude Polarizable Force Field for Small Molecules Drude General Force Field (DGenff)

      Chatterjee, Payal; MacKerell, Alexander D., Jr. (2020)
      The classical Drude oscillator polarizable force field offers an explicit treatment of induced electronic polarization presently not addressed in the commonly used additive force fields. Such an empirical approach leads to an improved and more accurate representation of electrostatic interactions in Molecular Mechanics and Molecular Dynamics (MD) simulations. The Drude Polarizable Force Field presently include topologies and parameters for biomolecules such as proteins, lipids, carbohydrates, and nucleic acids along with a limited set of small molecules. The present research is an effort to expand the existing Drude-oscillator based polarizable force field of CHARMM for general small drug like molecules – Drude General Force Field (DGenFF). A thorough development of such a force field will allow users to use polarizable force fields for drug design and other chemical fields.