Publication Category: Drug Design

  • Adjuvant-Pulsed mRNA Vaccine Nanoparticle for Immunoprophylactic and Therapeutic Tumor Suppression in Mice

    Biomaterials, 2020, 120431

    Synthetic mRNA represents an exciting cancer vaccine technology to the implementation of effective cancer immunotherapy. However, inefficient in vivo mRNA delivery along with a requirement for immune co-stimulation present major hurdles to achieving anti-tumor therapeutic efficacy. Here, we demonstrate a proof-of-concept adjuvant-pulsed mRNA vaccine nanoparticle (NP) that is composed of an ovalbumin-coded mRNA and a palmitic

  • Lipidation Approaches Potentiate Adjuvant-Pulsed Immune Surveillance: A Design Rationale for Cancer Nanovaccine

    Bioeng. Biotechnol., 8 2020, 787

    Adjuvant-pulsed peptide vaccines hold great promise for the prevention and treatment of different diseases including cancer. However, it has been difficult to maximize vaccine efficacy due to numerous obstacles including the unfavorable tolerability profile of adjuvants, instability of peptide antigens, limited cellular uptake, and fast diffusion from the injection site, as well as systemic adverse

  • Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations

    ACS Omega 2017, 2, 8, 4760–4771

    Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We

  • Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4

    Sci Rep 5, 16924

    Inhibition of cancer-promoting kinases is an established therapeutic strategy for the treatment of many cancers, although resistance to kinase inhibitors is common. One way to overcome resistance is to target orthogonal cancer-promoting pathways. Bromo and Extra-Terminal (BET) domain proteins, which belong to the family of epigenetic readers, have recently emerged as promising therapeutic targets in

  • Accurate Binding Free Energy Predictions in Fragment Optimization

    J. Chem. Inf. Model. 2015, 55, 11, 2411–2420

    Predicting protein–ligand binding free energies is a central aim of computational structure-based drug design (SBDD) — improved accuracy in binding free energy predictions could significantly reduce costs and accelerate project timelines in lead discovery and optimization. The recent development and validation of advanced free energy calculation methods represents a major step toward this goal. Accurately

  • Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus

    ACS Chem. Biol. 2013, 8, 12, 2744–2752

    Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and

  • Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design

    J. Chem. Theory Comput. 2013, 9, 12, 5693–5705

    Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the molecular level, drug resistance reflects a subtle change in the balance of molecular

  • Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S

    Biochemistry 2013, 52, 10, 1725–1736

    A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type

  • Rational Approaches to Improving Selectivity in Drug Design

    J. Med. Chem. 2012, 55, 4, 1424–1444

    Widely Cited

    Appropriate tuning of binding selectivity is a primary objective in the discovery and optimization of a compound on the path toward developing a drug. The environment in which drugs act is complex, with many potential interaction partners. Proteins, DNA, RNA, lipids, sugars, metabolites, and other small molecules all have the potential to interact with a

  • Computational Approaches for Fragment-Based and De Novo Design

    Current Topics in Medicinal Chemistry 10 (1), 14-32

    Fragment-based and de novo design strategies have been used in drug discovery for years. The methodologies for these strategies are typically discussed separately, yet the applications of these techniques overlap substantially. We present a review of various fragment-based discovery and de novo design protocols with an emphasis on successful applications in real-world drug discovery projects.