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At present we have a number of targets that offer progress in areas as diverse
as disease management to biomaterials development.
Novel Opioid Receptor
Active Agents
Our laboratory has discovered (worldwide
patent pending) a new class of small-molecule compounds, structurally distinct
from morphine-like opioids, that exhibit high
(nanomolar) binding affinity and selectivity for the opioid receptors.
These compounds can be chemically synthesized in high yield by a facile reaction
that is amenable to large-scale parallel synthesis. Potential therapeutic
applications
include analgesics, immunomodulatory agents, and treatments for narcotic
addiction. (Top)
Tubulin Ligands as Anti-Cancer Therapeutic Agents
One of our new initiatives
is the rational design of small-molecule tubulin-binding compounds as potential
anti-cancer therapeutic agents. These compounds are
structural analogues of the opioid receptor active agents mentioned above,
thus synthesis and biological evaluation is underway. (Top)
Na, K-ATPase Inhibitors for the Therapeutic Treatment of Cardiovascular
Diseases
Our laboratory has developed (patent pending) a structural model for
human Sodium Potassium (Na, K-) ATPase, the target for cardioglycosides such
as
digoxin and digitoxin which are “first line” treatments for congestive
heart failure and related conditions. Unfortunately, these two cardioglycosides
have narrow therapeutic indices resulting in severe toxic side effects. Based
on our structural model, together with interpretation of biological data,
we have elucidated the putative mechanism of action of these cardioglycosides
to guide the rational design of a new generation of effective yet safer therapeutic
agents.
Three-Dimensional
Quantitative Structure-Activity Relationship Study of the Inhibition
of the Na+,K+-ATPase by Cardiotonic Steroids Using Comparative
Molecular Field Analysis, C. D. Farr, C. Burd, M. R. Tabet, X. Wang, W. J.
Welsh, and W. J. Ball, Jr., Biochemistry, 41, 1137-1148 (2002).
Three-Dimensional
Quantitative Structure-Activity Relationship Analysis of Ligand Binding
to Human Sequence Antidigoxin Monoclonal Antibodies Using
Comparative Molecular Field Analysis, Farr, C. D.; Tabet, M. R.; Ball, W.
J., Jr.; Fishwild, D. M.; Wang, X.; Nair, A. C.; Welsh, W. J.; J. Med. Chem.;
45(15); 3257-3270 (2002).
Immunotoxicotherapy with Human Anti-drug Antibodies, W. J. Ball, S. Paula,
C. Farr, D. Williams, W. J. Welsh, A. B. Norman, Human Antibodies 12: 27-30
(2003).
(Top)
Nuclear Hormone Receptors
The nuclear receptors, such as the estrogen receptor
(ER) and androgen receptor (AR) are hormone-dependent transcription factors
that control many reproductive,
developmental, and metabolic functions in humans and wildlife. Our laboratory
has developed computer-based molecular models to guide the discovery of
novel therapeutic agents for the treatment of pathologies such as breast cancer
and prostate cancer that are mediated through nuclear receptors. Another
focus of study is the steroid & xenobiotic receptor (SXR), a nuclear
receptor that has been implicated in adverse drug-drug interactions and multi-drug
resistance (MDR).
Quantitative
Structure-Activity Relationship Studies of Estrogen Receptor Binding Affinity, W. Tong, R. Perkins, R. Strelitz, E. R. Collantes, S. Keenan,
W. J. Welsh, and D. M. Sheehan, Environmental Health Perspectives, 105, 1116-1124
(1997).
QSAR
Models for Binding Estrogenic Compounds to the a and b Estrogen Receptors,
W. Tong, R. Perkins, L. Xing, W. J. Welsh, and D. M. Sheehan, Endocrinology,
138, 4022-4025 (1997).
Comparison of Estrogen Receptors a and b Based on Comparative Molecular Field
Analysis (CoMFA), L. Xing and W. J. Welsh, W. Tong, R. Perkins, and D. M. Sheehan,
SAR and QSAR in Environmental Research, 10, 215-237 (1999).
The Estrogen Knowledge Base (EKB), a Prototype Toxicological
Knowledge Base for Endocrine Disrupting Compounds, R. Perkins, J. Anson,
W. Branham,
H. Fang, W. Tong, W. J. Welsh, Y. Chen, J. Meehan, M. Jackson, R. Nossaman,
L. Shi, and D. Sheehan, (J. D. Walker, Ed.); SETAC 2000.
Determination
of Vaporization Enthalpies of Polychlorinated Biphenyls by Correlation
Gas Chromatography, S. Puri, J. S. Chickos, and
W. J. Welsh, Analytical Chemistry, 73, 1480-1484 (2001).
Homology
Modeling of the Estrogen Receptor Subtype b (ER-b) and Prediction of
Ligand Binding Affinities, R. K. DeLisle, S.J. Yu, and W.J. Welsh, J Mol
Graph Model, 20, 155-167 (2001).
Three-Dimensional
Quantitative Structure-Property Relationship Models for Predicting Thermodynamic
Properties of Polychlorinated Biphenyls: Sublimation,
S. Puri, J. Chickos, and W. J. Welsh, J Chem Inf Comp Sci, 42, 109 (2002).
Three-Dimensional
Quantitative Structure-Property Relationship Models for Predicting the
Thermodynamic Properties of Polychlorinated Biphenyls
(PCBs): vaporization,
S. Puri, J. S. Chickos, and W. J. Welsh, J Chem Inf Comp Sci, 42(2), 299-304
(2002).
Three-Dimensional Quantitative Structure-Property Relationship (QSPR) Models
for Predicting the Thermodynamic Properties of Polychlorinated Biphenyls (PCBs):
Vaporization, S. Puri, J. Chickos, and W. J. Welsh, J Chem Inf Comp Sci, 42,
209-214 (2002).
Influence
of the Structural Diversity of Data Sets on the Statistical Quality of
Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR)
Models: Predicting the Estrogenic Activity of Xenoestrogens, Yu, S. J.; Keenan,
S. M.; Tong, W.; Welsh, W. J.; Chem. Res. Toxicol.; 15(10); 1229-1234 (2002).
Three-Dimensional
Quantitative Structure-Property Relationship Models for Predicting the
Thermodynamic Properties of Polychlorinated Biphenyls (PCBs):
(III) Enthalpy of Fusion and Their Application to Estimates of Sublimation
and Aqueous Solubilities, S. Puri, J. Chickos, and W. J. Welsh, J Chem Inf
Comput Sci, 43, 55-62 (2003).
Interaction
of Organophosphate Pesticides and Related Compounds with the Androgen Receptor, H. Tamura, H. Yoshikawa, A. M. Richard, S. M. Ross, R. DeLisle, W.
J. Welsh, and K. W. Gaido, Environ Health Persp, 111, 1-8 (2003).
QSAR
Models in Receptor-Mediated Effects: The Nuclear Receptor Superfamily,
H. Fang, W. Tong, W. J. Welsh, and D. M. Sheehan, Journal of Molecular Structure
(Theochem), 622, 113-125 (2003). Structure-Activity Relationship Approaches
and Applications, W. Tong, W. J. Welsh, L. Shi, H. Fang, R. Perkins, Environ
Toxicol Chem, 22(8), 1680-95 (2003).
Quantitative
Structure-Activity Relationship Methods: Perspectives on Drug Discovery
and Toxicology, R. Perkins, H. Fang, W. Tong, W. J. Welsh, Environ
Toxicol Chem, 22, 1666-79 (2003).
Computational
Models for Predicting Binding Affinities of Ligands for the Wild-Type
Androgen Receptor and a Mutated Variant Associated with Prostate
Cancer, N. Ai, RK DeLisle, S. Yu, W. J. Welsh, Chem. Res. Toxicol, 16, 1652-1660
(2003).
Highly
Chlorinated PCBs Inhibit the Human Xenobiotic Response Mediated by the
Steroid and Xenobiotic Receptor (SXR), M M Tabb, V Kholodovych, F Grun,
C Zhou, W J Welsh, and B Blumberg, Environmental Health Perspectives, 112 (2),
163-170 (2004).
(Top)
Kinase Inhibitors for the Treatment of Malaria
Our laboratory has constructed
structural models for three novel kinases (PfPK5, PfPK6, Pfmrk) that play
an essential role in the life cycle of Plasmodium
(P.) falciparum, the major causative parasitic agent responsible for over
95% of the 1-3 million worldwide deaths resulting annually from malarial
infection. Using this structural information for PfPK5, PfPK6 and Pfmrk,
we implementing a strategy for the discovery of potent and selective P.
falciparum kinase inhibitors as therapeutic agents for the treatment of malaria.
Characterization
of the Plasmodium falciparum PK5 ATP-Binding Site: Implications for the
Design of Novel Antimalarial Agents, J Mol Graph Model, S. M. Keenan,
W. J. Welsh, 22, 241-247 (2003)
(Top)
Bio-Therapeutic Effects of Green Tea
Overexpression of the enzyme DNA methyl
transferase (DNMT) in many cancerous tumors leads to the “silencing” of
genes associated with programmed (i.e., normal) cell death. Interestingly,
this undesirable
process is blocked
and even reversed by one or more ingredients found in green tea. Our
laboratory has employed computer modeling to elucidate the mechanism
by which DNMT
is inhibited by epigallocatechin gallate (EGCG), the biologically active
ingredient
in green tea. We are now using this information to design novel DNMT
inhibitors for various therapeutic applications.
Tea
Polyphenol (-)-Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase
and Reactivates Methylation-Silenced Genes in Cancer Cell Lines, M Z Fang,
Y Wang, N Ai, Z Hou, Y Sun, H Lu, W J Welsh, C S Yang, Cancer Research 63,
7563-7570 (2003)
(Top)
Optimal Design of Biomaterials
In conjunction with Dr. Joachim Kohn (Rutgers Univ. & NJ Center
for Biomaterials), we are applying rational computer-guided molecular
modeling tools toward the optimal design of polymers for biomedical
applications such as implants for tissue regeneration.
Phase
Equilibria of Polyetherbutylene in Diisodiketone Determined
by Molecular Mechanics, S. O. Jonsdittir and W. J. Welsh,
Computational and Theoretical Polymer Science, 10, 125-131 (2000).
(Top)
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