About

The Brown Lab is at the forefront of molecular modeling and computational biology, fostering collaborations both on campus at Virginia Tech and with other leading universities. We use our expertise in computational analysis to consult with dozens of research groups, bridging the gap between traditional wet lab techniques and computational methodologies to deepen our understanding of biological systems. We specialize in exploring protein structure-function relationships and advancing computer-aided drug discovery, with a focus on amyloids, kinases, and RNA viruses. We offer rich undergraduate research opportunities through our innovative experiential learning program.

Research topics

• Biology
• Virology
• Biochemistry
• Cell biology
• Cancer research
• Chemistry
• Genetics
• Immunology
• Computational biology
• Pharmacology

Selected publications

• Development of semisynthetic blasticidin S analogs with potent and fast-killing anti-malarial activity

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-13

  articleOpen access

  ABSTRACT Protein synthesis represents an attractive target space for the development of anti-malarials with novel modes of action. Natural-product inhibitors of the eukaryotic 80S ribosome can have potent anti-malarial activity but are often poorly selective due to mammalian cytotoxicity. Blasticidin S (BlaS) is a microbially-produced natural product that broadly inhibits prokaryotic and eukaryotic protein synthesis by binding to the ribosomal peptidyl transferase center. In this study, we explored the potential for improving the anti-malarial potency and selectivity of the blasticidin S scaffold with semi-synthetic analogs that are modified at the C6’ and C4 sites. The two best analogs were two orders of magnitude more potent than BlaS against Plasmodium falciparum drug-sensitive and -resistant lines while displaying low cytotoxicity towards mammalian cells. These analogs exhibited improved kinetics of inhibition of protein synthesis in cultured parasites and blocked the development of asexual stages expressing the plasmodial surface anion channel, a transporter required for nutrient acquisition and BlaS uptake. They also exhibited a dramatically improved speed of killing over BlaS. Molecular docking analysis revealed that these analogs are able to form more interactions with the P. falciparum ribosomal peptidyl transferase center than is BlaS, which is consistent with their increased potency. Together, these studies demonstrate the feasibility of generating BlaS analogs with potent anti-malarial activity and provide a roadmap for further development.

  PublisherDOI

• 380 Uncharacterized MYH9 Germline Mutations in a Microcystic Adnexal Carcinoma Mimicker: Benign Deep Syringoid Ductal Proliferation (BDSDP) with Elastic Fiber Aggregation

  Laboratory Investigation · 2026-03-01

  article
  PublisherDOI

• MDA-9/Syntenin small molecule inhibitor IVMT-Rx-4 blocks prostate cancer bone metastasis

  Pharmacological Research · 2026-03-21

  articleOpen access

  Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). This process originates through an interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche. Melanoma differentiation associated gene-9 ( mda-9/Syntenin ) is a pro-metastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. MDA-9/Syntenin coordinates the interactions between tumor cells and BM-MSCs, which promote establishment of metastatic tumors in the bone niche. Considering the importance of protein-protein interactions in regulating MDA-9/Syntenin functions, we focused on developing small molecule inhibitors of these interactions. We describe the translational potential of IVMT-Rx-4, an intermediate synthesis product of PDZ1i, in inhibiting PC bone metastasis. IVMT-Rx-4 has similar bioactivity as PDZ1i but with improved druggable properties, e.g., higher solubility and lower efflux. It promotes potent anti-invasive and anti-metastatic effects by inhibiting the MDA-9/Syntenin dependent tumor-derived platelet derived growth factor, PDGF-AA, and its related signalling in BM-MSCs. In addition, the combination of IVMT-Rx-4 and docetaxel enhances survival in experimental bone metastasis models. These observations reinforce the concept that together with metastasis suppression, IVMT-Rx-4 can boost the effectiveness of standard-of-care treatment. Collectively, the present work provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC. • Developing effective therapies for prostate cancer bone metastasis, a final stage of PC progression leading to patient morbidity and without effective treatments, is a medical priority. • IVMT-Rx-4, an intermediate product of PDZ1i synthesis, surprisingly showed anti-invasive and anti-metastatic properties against PC cell lines with improved “drug-like” properties vs. PDZ1i, e.g., higher aqueous solubility, lower efflux, and a similar lack of toxicity. • IVMT-Rx-4 blocks protein-protein interactions that specifically interrupt MDA-9/Syntenin signaling, leading to an inhibition in progression of PC cells to bone metastasis. • IVMT-Rx-4 augments beneficial outcomes of docetaxel, a standard-of-care chemotherapy for advanced PC patients, in terms of promoting survival gains in both syngeneic and athymic nude mice injected with murine and human advanced PC cell lines, respectively.

  PublisherDOI

• Engineering Pleuromutilin Epimers to Engage an Unexploited Ribosomal Binding Pocket

  ChemRxiv · 2025-05-26

  preprintOpen access

  Optimizing the bioactivity of natural product–derived antibiotics is an inherently challenging process, particularly when targeting complex macromolecular assemblies like the bacterial ribosome. Yet such efforts are essential for the rational design and development of next-generation antibiotics. Pleuromutilin derivatives are of particular value given their recent approval for systemic human use and low frequency of resistance development. While most efforts have focused on C22-substituted thioglycolates, identifying new functionalization sites is critical for advancing this antibiotic class. Leveraging structural insights from computational modeling, we identified C12 as a novel derivatization site amenable to divergent semisynthetic modification. To access this site, we epimerized C12 and applied an optimized anti-Markovnikov hydroazidation strategy to activate C20 for rapid diversification into a triazole library using CuAAC click chemistry. Biological evaluation confirmed that aromatic triazole substituents exhibited the best activity. Docking analysis guided structure-based refinements, resulting in derivatives with sub-ug/mL antimicrobial potency. X-ray crystallography revealed that the novel triazole arm binds in a previously unexploited region of the ribosomal A-site, with mechanism-of-action and toxicity studies confirming selectivity. Notably, C22 functionality did not impact activity. Collectively, these findings define a new ribosomal binding region for pleuromutilin and provide a framework for further structurally and computationally guided semisynthetic derivatization.

  PublisherOA PDFDOI

• BPS2025 - Probing the influence of sequence on cytotoxic and functional amyloid oligomer conformations

  Biophysical Journal · 2025-02-01

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Robustness in biomolecular simulations: Addressing challenges in data generation, analysis, and curation

  Cell Reports Physical Science · 2025-05-01 · 5 citations

  articleOpen access1st authorCorresponding

  Computational simulations of biomolecules provide a wealth of information about the thermodynamic landscape of biologically important systems, kinetics of important cellular processes, and the biophysical basis of life. Despite the ubiquity of molecular simulations in biophysical literature, major challenges persist for new practitioners entering the field, and even for experienced computational scientists, in maintaining and distributing their simulation outcomes. Here, we summarize critical obstacles encountered when performing biomolecular simulations and provide best practices for performing simulations that are robust, reproducible, and hypothesis-driven. We also discuss practices that promote improved reproducibility and accessibility using reliable tools and databases.

  PublisherDOI

• Biogenic Amine-Containing 1,4-Naphthoquinones Mediate Extracellular Electron Transfer in <i>Lactiplantibacillus plantarum</i>

  Organic Letters · 2025-09-08 · 1 citations

  articleOpen access

  , a lactic acid gut bacterium, uses exogenous quinones to facilitate extracellular electron transfer (EET) via type II NADH dehydrogenase (Ndh2). To probe Ndh2 specificity, we designed and evaluated a library of biogenic amine-substituted 1,4-naphthoquinones in an Ndh2-dependent EET assay. Analysis of mediator Ndh2 binding interactions revealed that activity correlates with key binding interactions. Specifically, mediators containing aromatic substitutions elicit favorable Ndh2 interactions, promoting EET.

  PublisherDOI

• BPS2025 - Biophysical insights into allosteric modulation and inhibition of viral proteases using MD simulations

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans

  PLoS neglected tropical diseases · 2025-12-16

  articleOpen accessCorresponding

  Cryptococcosis is an opportunistic fungal infection affecting individuals with compromised immunity, particularly those with HIV. The limited accessibility to effective treatments and treatment-related toxicities underline the need for more effective therapeutic options. In this study, we conducted a whole-cell screening of ~ 3,700 FDA-approved drugs and clinical molecules against the Cryptococcus neoformans H99 strain. The anti-mycobacterial agent SQ109 was identified as one of the most potent hits, with broad antifungal activity. SQ109 exhibited potent activity against Cryptococcus spp., with an MIC90 of 4 μg/mL. In the time-kill assay, SQ109 demonstrated a fungicidal activity on proliferating cryptococcal cells in a concentration-dependent manner. Unlike fluconazole (FLC) and flucytosine (5-FC), C. neoformans showed a negligible tendency to develop resistance to SQ109 during frequent passaging. Furthermore, SQ109 exhibited a potent efficiency in the murine model of cryptococcal infection, resulting in a 50% survival rate among animals treated with 25 mg/kg for 10 consecutive days. The transcriptomic analysis revealed that SQ109 disrupts ergosterol biosynthesis, affecting membrane integrity and oxidative homeostasis. Additionally, molecular docking and structural analysis indicated that squalene synthase protein ERG9 is the most likely target of SQ109 within the ergosterol biosynthesis machinery of cryptococcal cells. Notably, SQ109 potentiates the activity of the standard antifungal FLC, as well as other ergosterol inhibitors, with a fractional inhibitory concentration Index (ΣFICI) ranging from 0.38 to 1. These findings highlight the therapeutic potential of SQ109 in combating cryptococcal infections, both as a standalone therapy and as an adjuvant to FLC monotherapy.

  PublisherDOI

• BPS2025 - Characterizing oligomeric amyloid-β42 and POPC interactions through molecular dynamics: A computational approach for understanding Alzheimer’s disease

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

Frequent coauthors

• John Gonzalez

  Trinity Washington University

  72 shared

• Jonathan Briganti

  Radford University

  45 shared

• Erin Drolet

  Radford University

  38 shared

• David R. Bevan

  Virginia Tech

  38 shared

• Amanda Raimer

  Virginia Tech

  36 shared

• Jeanne Mekolichick

  Concord University

  36 shared

• Brian Taylor

  36 shared

• Jamie K. Lau

  Towson University

  36 shared

Labs

• Brown LabPI

Education

• Ph.D., Biochemistry

  Virginia Polytechnic Institute and State University

  2016

• B.S., Biochemistry, Physics

  Roanoke College

  2010