VCU Center for Drug Discovery

Cancer continues to be challenging to public health, with nearly 2,000 deaths and 5,000 new cases per day. Center researchers focus on the discovery of new anti-cancer targets as personalized medicine and new approaches for the diagnosis, prevention, and treatment of cancer.  The following are some highlights.

• Potent inhibitors (IC₅₀ = 60 nM) have been developed to specifically target protein N-terminal methyltransferase 1, which represents a potential new approach to personalized cancer therapy including melanoma, colorectal and thyroid cancer ... Rong Huang
• G2.2 and its analogs structurally mimic heparin hexasaccharide; selectively inhibit cancer stem cells growth and self-renewal in colorectal, pancreatic and breast cells through activation of p38 MAPK involving IGF-1R and FGFR; G2.2 inhibits CSCs proliferation in mice xenografts ... Umesh Desai
• Irreversible inhibitors for the AGC kinase as an activity-based protein profiling to selectively identify and quantify the activated form in cells for detection and diagnosis ... Keith Ellis
• A small molecule called NT-7-16 has been identified as a microtubule destabilizer (30 nM potency) and anti-proliferation agent (10 nM potency) by binding in tubulin’s colchicine binding site; indications are that it overcomes taxol resistance. ISB3D researchers are leading the drug design efforts to discover even more efficacious agents ... Glen Kellogg
• The research in Dr. Jiong Li’s lab primarily aims to decipher the molecular mechanisms underlying dysregulated transcription that drive tumorigenesis and promote drug resistance of head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). We employ a combination of biochemical and biophysical methods, along with animal models, to investigate oncogenic transcription factors, including FOSL1, NF-kB, and β-catenin. Additionally, we are collaborating with structural biologists and medicinal chemists to develop innovative therapeutics, such as PROTAC degraders and small molecule inhibitors, selectively targeting transcriptional dysregulation in HNSCC and CRC.

Cognitive disorders become an increasingly important public health problem. Center researchers are working on new mechanism and therapeutic approaches to diseases like Alzheimer’s disease. The following are some highlights.

• Interactions of the Alzheimer’s amyloid peptide Aβ in its different forms with inflammatory proteins and the effects of these interactions on reactive oxygen release from activated rodent microglia ... H. Tonie Wright
• High-resolution X-ray crystallographic and cryo-electron microscopic structures of membrane proteins like the translocator protein for Alzheimer’s Disease drug discovery and development ... Youzhong Guo
• The main research interests in S. Zhang's laboratory are small molecule drug discovery and development for neurodegenerative diseases and inflammatory diseases using cutting edge technologies of medicinal chemistry. The currently ongoing research projects are:
  • To design and develop small molecules that target mitochondria complex I as neuroprotective agents for AD and other neurodegenerative diseases
  • To design and develop novel NLRP3 and GSDMD inhibitors as pharmacological tools and potential therapeutic agents for neurodegenerative disorders

Blood and cardiovascular diseases are the underlying cause of ~50% of all disease-related deaths in the US. Center researchers have developed several promising compounds as anticoagulants and antisickling agents. The following are some highlights.

• Four molecules (SPGG, SCI, SMI and SG-09) identified as preventing thrombosis at 25 – 250 g per mouse (1.25–12.5 mg/kg) dose as selective (>200-fold selectivity) factor XIa targeting anticoagulants through an allosteric inhibition mechanism ... Umesh Desai
• Allosteric modifiers of hemoglobin with nitric oxide releasing ability, which can increase both erythrocyte mobility and tissue oxygen and have potential application in stroke, myocardial infraction, and vasoconstriction prevention ... Martin Safo
• Structure-function studies of hemoglobin and rational design of antisickling agents to treat sickle cell disease; Two drugs have been developed, one currently in phase II clinical study, and the other preclinical study ...  Martin Safo

The majority of chronic tobacco smokers develop emphematous lung, resulting in chronic obstructive pulmonary diseases (COPDs). No treatment is available to date that cures emphematous lung and all current treatments provide only symptomatic relief.

• Researchers at the center have developed novel molecules that not only prevent but cure emphysema/COPD ... Umesh Desai in collaboration with Masahiro Sakagami in the Dept. of Pharmaceutics, School of Pharmacy

• S. Zhang's laboratory is developing novel PET radiotracers by targeting NLRP3, GSDMD, and complex I as potential biomarkers to aid drug discovery and evaluations.

Infectious diseases pose a great threat to human health. Pathogens continually evolve to anti-infectious agents, making future generations more difficult to treat. This requires the continued development of new strategies to fight and prevent infection.   

• Development of a recombinant hepadnaviral core protein engineered to present malaria B cell and T cell epitopes in a highly immunogenic form that can function as a vaccine to elicit protective antibodies in recipients ... Darrell Peterson
• PHE as an anti-influenza agent that disrupts the M1 layer; it inhibits M1 oligomerization at 1-5 M and inhibits multiple viral strains including H1N1, H3N2, and H5N1 ... Umesh Desai and Martin Safo
• Many Gram-negative pathogenic bacteria, such as enteropathogenic E. coli, Salmonella enterica serotype Typhi and Yersinia pestis, use a conserved virulence apparatus called the Type III Secretion System (TTSS) to infect eukaryotic host cells. The synthesis of new and more potent TTSS inhibitors that function by preventing pathogenic bacteria from using their TTSS to cause infection is being pursued at the Center, as well as studies to more precisely define their molecular targets ... Aaron May
• Conjugation is a process used by many Gram-negative and Gram-positive bacteria to share antibiotic resistance genes, even if they have not been previously exposed to a specific drug.  This process is enabled by an apparatus called the Type IV Secretion System (T4SS), and inhibiting T4SS is a next-generation strategy to limit antibiotic resistance gene transfer ... Aaron May
• Structural studies of a S. aureus protease essential for ribosomal maturation and bacterial viability is being investigated as a basis for inhibitor design and screening ... Darrell Peterson, J. Neel Scarsdale, H. Tonie Wright in collaboration with Gail Christie in the Dept. of Microbiology, School of Medicine
• Human cytomegalovirus (CMV) is a significant human pathogen with a need for safer and more effective therapeutics. Center members are determining the crystal structure of the viral nuclease, which will form a basis for understanding the biochemical activities of the nuclease, its role in viral replication, and for exploiting the nuclease as a target for anti-viral drug discovery ... Martin Safo, Glen Kellogg in collaboration with Michael McVoy in the Dept. of Pediatrics, School of Medicine
• Dr. Chunhao Li‘s group studies bacterial genetics, physiology and host-pathogen interactions by using an approach of genetics, biochemistry, biophysics, cell biology, structural biology and animal models. His current research interest mainly focuses on three human pathogens: Borrelia burgdorferi, the causative agent of Lyme disease, Treponema denticola and Porphyromonas gingivalis, two keystone pathogens associated with periodontitis. His research has been found by NIAID and NIDCR since 2008
• Nitric oxide (NO) is a natural broad-spectrum antimicrobial. Dr. Xuewei Wang’s group designs innovative drug formulations that enable controlled nitric oxide release from medical implants, including catheters, cannulas and sensors. By releasing nitric oxide at the implant surface, these materials effectively inhibit the growth of both planktonic and biofilm bacteria, helping to prevent device-associated infections and related complications.
• The malaria parasites vary their surface proteins to avoid the host’s immune response, thereby perpetuating long-term infections. This so called “antigenic variation” is thought to be controlled by the NAD + -dependent histone deacetylase, PfSir2A, through epigenetic regulations. Therefore, pharmacological inhibition of PfSir2A may disrupt the mechanism of antigenic variation, and expose an extensive array of variants expressed on the surface of the parasites to stimulate broad, highly protective immunity. The study in Dr. Yana Cen’s lab has revealed new understandings on the regulation of PfSir2A activity, and new scaffolds for PfSir2A inhibitor. This is an exciting project that holds great potential for antimalarial drug discovery.

The opioid crisis has been going on in this country for more than thirty years. Development of novel and more effective treatments to counteract opioid addiction and overdose is imperative.

• In Yan Zhang's lab, we have been working on the development of mu opioid receptor modulators to treat opioid addiction and fentanyl specific counteracting agents to treat fentanyl overdose.
• Studies in Dr. Dukat’s lab involve investigation of existing agents, and development of novel compounds, for the treatment of neuropsychiatric disorders, pain, and substance abuse. Methods routinely employed include synthesis, computational techniques (e.g., graphics modeling and docking at selected receptors and transporters; SAR and QSAR studies), and in vitro and in vivo pharmacological assays to investigate action and mechanisms of action. Of current interest are serotonergic psychedelic agents for use in treatment-resistant depression, and structurally novel types of agents (developed in our laboratory) that act as monoamine transporter (MAT) reuptake inhibitors, and others that act at OCTs (organic cation transporters).
• Dr. Pagare’s research focuses on developing novel mu-opioid receptor (MOR) modulators to counteract the effects of synthetic opioids, with the goal of creating safer treatments for opioid use disorder (OUD) and overdose. The emergence of ultra-potent MOR agonists, including fentanyl and nitazene derivatives, has increasingly challenged the efficacy of traditional OUD therapeutics. To address this, we integrate computational modeling, chemical synthesis, and in vitro and in vivo studies to design MOR-selective bitopic ligands that engage both orthosteric and allosteric sites. These ligands serve as pharmacological probes and tools to investigate receptor activation and inhibition, with the potential to inform novel therapeutics for OUD, safer analgesics, and harm reduction strategies.

• Development of new and novel algorithms that are based on detecting and exploiting the underlying three-dimensional hydropathic interaction homologies within protein structure, which is a new strategy for protein structure prediction ... Glen Kellogg and J. Neel Scarsdale
• One of the evolving strategies for drug discovery is targeted inhibition of protein-protein interactions by small molecules. Unfortunately, the results to date have been unimpressive, and new approaches are necessary. Center researchers are exploring new theories and methods that exploit water, local pH and the hydrophobic effect ... Glen Kellogg, J. Neel Scarsdale in collaboration with Peter Uetz in the Center for the Study of Biological Complexity, Life Sciences
• Dr. Ka Un Lao’s research group focuses on integrating applied mathematics and machine learning with electronic structure theory to accelerate quantum chemistry calculations. These next-generation approaches significantly speed up quantum chemistry's core operations while maintaining chemical accuracy, enabling us to study larger and more complex systems. Specifically, our research is focused on three main directions: Integration of Grassmannians from differential geometry into quantum chemistry to enhance chemical discovery and improve the rational design of light-sensitive molecular devices; Integration of set theory-based fragmentation into quantum chemistry to enable accurate and efficient calculations of reaction and interaction energies in biological systems, offering valuable tools for studying enzymecatalyzed reactions and supporting new drug design efforts; Integration of machine learning data-driven models into quantum chemistry to address the scalability and transferability limitations of traditional machine learning models in predicting molecular properties.