William Welsh
Professor

UMDNJ
Department of Pharmacology
675 Hoes Lane
Piscataway, NJ 08854
(732) 235-3234
FAX - 4073
welshwj@umdnj.edu

Drug discovery. computer-aided molecular modeling and design. bioinformatics and cheminformatics

Our laboratory specializes in the development and application of computational tools in bioinformatics. cheminformatics. and computer-aided drug discovery. Examples of specific projects are described below.

Novel Opioid Receptor Active Agents

The aim of this project is the discovery of therapeutic agents that can alleviate pain as do narcotics but do not possess their addictive and other negative side effects. Potential therapeutic applications include analgesics. immunomodulatory agents for treating immune disorders. and new treatments for drug addiction. Our laboratory has already discovered and patented a new class of compounds. structurally distinct from morphine-like opioids. that exhibit high binding affinity for the opioid receptors.

Novel Na. K-ATPase inhibitors for the therapeutic treatment of cardiovascular diseases

Cardioglycosides such as digoxin and digitoxin. which are the drugs of choice for the clinical treatment of congestive heart failure. work by inhibiting Sodium Potassium (Na. K-) ATPase. Unfortunately. these cardioglycoside drugs have narrow therapeutic indices resulting in severe toxic side effects. Our laboratory has constructed a computer model of human Na. K-ATPase. thus guiding the rational computer-aided design of novel inhibitors that exhibit good potency yet low toxicity.

Computer Models for Predicting the Toxicology and Environmental Impact of Chemicals

Our laboratory is developing and applying computational tools useful for predicting the toxicology and environmental impact of chemicals that can interfere with our delicate endocrine system. in particular the estrogen receptor. androgen receptor. and the steroid & xenobiotic receptor. Our research has led to the discovery of new molecules for these receptors as potential therapeutic agents.

Discovery of Novel Anti-Malarial Agents

Plasmodium (P.) falciparum is responsible for the most severe of the 300 to 500 million clinical cases and for over 95% of the 1-3 million worldwide deaths resulting annually from malarial infection. The overall objective of this research project is to computer design. chemically synthesize. and biologically evaluate a series of novel P. falciparum kinase inhibitors as therapeutic agents for the treatment of malaria.

Selected Publications

Ekins S, Kholodovych V, Ai N, Sinz M, Gal J, Gera L, Welsh WJ, Bachmann K, Mani S. (2008)
Computational discovery of novel low micromolar human Pregane X receptor antagonists. Mol Pharmacol. Jun 25. [Epub ahead of print]

Kortagere S, Ekins S, Welsh WJ. (2008) Halogenated ligands and their interactions with amino acids: Implications for structure-activity and structure-toxicity relationships. J Mol Graph Model. Apr 10. [Epub ahead of print]

Chekmarev DS, Kholodovych V, Balakin KV, Ivanenkov Y, Ekins S, Welsh WJ. (2008) Shape signatures: New descriptors for predicting cardiotoxicity in silico. Chem Res Toxicol. May 8. [Epub ahead of print]

Kortagere S, Chekmarev D, Welsh WJ, Ekins S. (2008) New predictive models for blood-brain barrier permeability of drug-like molecules. Pharm Res. Apr 16. [Epub ahead of print]

Reschly EJ, Ai N, Welsh WJ, Ekins S, Hagey LR, Krasowski MD. (2008) Ligand specificity and evolution of liver X receptors. J Steroid Biochem Mol Biol. 110(1-2):83-94.

Reschly EJ, Ai N, Ekins S, Welsh WJ, Hagey LR, Hofmann AF, Krasowski MD. (2008) Evolution of the bile salt nuclear receptor FXR in vertebrates. J Lipid Res. 49(7):1577-87.

Fernández JR, Welsh WJ, Firestein BL. (2008) Structural characterization of the zinc binding domain in cytosolic PSD-95 interactor (cypin): Role of zinc binding in guanine deamination and dendrite branching. Proteins. 70(3):873-81.

Yoon S, Welsh WJ, Jung H, Yoo YD. (2007) CSSP2: An improved method for predicting contact-dependent secondary structure propensity. Comput Biol Chem. 31(5-6):373-7.

Kohn J, Welsh WJ, Knight D. (2007) A new approach to the rationale discovery of polymeric biomaterials. Biomaterials. 28(29):4171-7.

Woodard CL, Keenan SM, Gerena L, Welsh WJ, Geyer JA, Waters NC. (2007) Evaluation of broad spectrum protein kinase inhibitors to probe the architecture of the malarial cyclin dependent protein kinase Pfmrk. Bioorg Med Chem Lett. 17(17):4961-6.

Ekins S, Chang C, Mani S, Krasowski MD, Reschly EJ, Iyer M, Kholodovych V, Ai N, Welsh WJ, Sinz M, Swaan PW, Patel R, Bachmann K. (2007) Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites. Mol Pharmacol. 72(3):592-603.

Grace CR, Cowsik SM, Shim JY, Welsh WJ, Howlett AC. (2007) Unique helical conformation of the fourth cytoplasmic loop of the CB1 cannabinoid receptor in a negatively charged environment. J Struct Biol. 159(3):359-68.

Kovalishyn VV, Kholodovych V, Tetko IV, Welsh WJ. (2007) Volume learning algorithm significantly improved PLS model for predicting the estrogenic activity of xenoestrogens. J Mol Graph Model. 26(2):591-4.

Zhang Q, Peng Y, Wang XI, Keenan SM, Arora S, Welsh WJ. (2007) Highly potent triazole-based tubulin polymerization inhibitors. J Med Chem. 50(4):749-54.

Wang CY, Ai N, Arora S, Erenrich E, Nagarajan K, Zauhar R, Young D, Welsh WJ. (2006) Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach. Chem Res Toxicol. 19(12):1595-601.

Kortagere S, Welsh WJ. (2006) Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors. J Comput Aided Mol Des. 20(12):789-802.

Haimovich AD, Byrne B, Ramaswamy R, Welsh WJ. (2006) Wavelet analysis of DNA walks.
J Comput Biol. 13(7):1289-98.

Meek PJ, Liu Z, Tian L, Wang CY, Welsh WJ, Zauhar RJ. (2006) Shape Signatures: speeding up computer aided drug discovery. Drug Discov Today. 11(19-20):895-904.

Amin EA, Welsh WJ. (2006) A preliminary in silico lead series of 2-phthalimidinoglutaric acid analogues designed as MMP-3 inhibitors. J Chem Inf Model. 46(5):2104-9.

Amin EA, Welsh WJ. (2006) Highly predictive CoMFA and CoMSIA models for two series of stromelysin-1 (MMP-3) inhibitors elucidate S1' and S1-S2' binding modes. J Chem Inf Model. 46(4):1775-83.

Zhang Q, Keenan SM, Peng Y, Nair AC, Yu SJ, Howells RD, Welsh WJ. (2006) Discovery of novel triazole-based opioid receptor antagonists. J Med Chem. 49(14):4044-7.

Wang CY. Li CW. Chen JD. Welsh WJ. (2006) Structural model reveals key interactions in the assembly of the pregnane X receptor/corepressor complex. Mol Pharmacol. 69(5):1513-7.

Jornsten R. Wang HY. Welsh WJ. Ouyang M. (2005) DNA microarray data imputation and significance analysis of differential expression. Bioinformatics. 21(22):4155-61.

Peng Y. Keenan SM. Welsh WJ. (2005) Structural model of the Plasmodium CDK. Pfmrk. a novel target for malaria therapeutics. J Mol Graph Model. 24(1):72-80.

Peng Y. Keenan SM. Zhang Q. Welsh WJ. (2005) 3D-QSAR comparative molecular field analysis on delta opioid receptor agonist SNC80 and its analogs. J Mol Graph Model. 24(1):25-33.

Sun Y. Welsh WJ. Latour RA. (2005) Prediction of the orientations of adsorbed protein using an empirical energy function with implicit solvation. Langmuir. 21(12):5616-26.

Nur-E-Kamal A. Zhang A. Keenan SM. Wang XI. Seraj J. Satoh T. Meiners S. Welsh WJ. (2005) Requirement of activated Cdc42-associated kinase for survival of v-Ras-transformed mammalian cells. Mol Cancer Res. 3(5):297-305.

Keenan SM. DeLisle RK. Welsh WJ. Paula S. Ball WJ Jr. (2005) Elucidation of the Na+. K+-ATPase digitalis binding site. J Mol Graph Model. 23(6):465-75.

Chen D. Wang CY. Lambert JD. Ai N. Welsh WJ. Yang CS. (2005) Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure-activity relationship and molecular-modeling studies. Biochem Pharmacol. 69(10):1523-31.

Yoon S. Welsh WJ. (2005) Rapid assessment of contact-dependent secondary structure propensity: relevance to amyloidogenic sequences. Proteins. 60(1):110-7.

Zhang Q. Yoon S. Welsh WJ. (2005) Improved method for predicting beta-turn using support vector machine. Bioinformatics.21(10):2370-4.

Lambert JD. Chen D. Wang CY. Ai N. Sang S. Ho CT. Welsh WJ. Yang CS. (2005) Benzotropolone inhibitors of estradiol methylation: kinetics and in silico modeling studies. Bioorg Med Chem. 13(7):2501-7.

Peng Y. Keenan SM. Zhang Q. Kholodovych V. Welsh WJ. (2005) 3D-QSAR comparative molecular field analysis on opioid receptor antagonists: pooling data from different studies. J Med Chem. 48(5):1620-9.

Keenan SM. Geyer JA. Welsh WJ. Prigge ST. Waters NC. (2005) Rational inhibitor design and iterative screening in the identification of selective plasmodial cyclin dependent kinase inhibitors. Comb Chem High Throughput Screen. 8(1):27-38.

Nagarajan K. Zauhar R. Welsh WJ. (2005) Enrichment of ligands for the serotonin receptor using the Shape Signatures approach. J Chem Inf Model. 45(1):49-57.

Yoon S. Welsh WJ. (2004) Detecting hidden sequence propensity for amyloid fibril formation. Protein Sci. 13(8):2149-60.

Smith JR. Knight D. Kohn J. Rasheed K. Weber N. Kholodovych V. Welsh WJ. (2004) Using surrogate modeling in the prediction of fibrinogen adsorption onto polymer surfaces. J Chem Inf Comput Sci. 44(3):1088-97.

Amin EA. Harris WR. Welsh WJ. (2004) Identification of possible kinetically significant anion-binding sites in human serum transferrin using molecular modeling strategies. Biopolymers. 73(2):205-15.

Tabb. M M . Kholodovych. V. Grun. F. Zhou. C. Welsh. W J and Blumberg. B (2004). Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR). Environmental Health Perspectives 112 (2):163-170.

Ouyang. M. Welsh. WJ and Georgopoulos. P (2004). Gaussian mixture clustering and imputation of microarray data. Bioinformatics (12)20:917-23.

Paula. S. . Tabet. M.. Keenan. S.. Welsh. W. J. and Ball Jr.. W. J. (2003). Three-dimensional structure-activity relationship modeling of cocaine-binding to two monoclonal antibodies. J Mol Biol 325:515-530.

Tamura. H.. Yoshikawa. H.. Richard. A. M.. Ross. S. M.. DeLisle. R.. Welsh. W. J. and Gaido. K. W. (2003). Interaction of organophosphate pesticides and related compounds with the androgen receptor. Environ Health Persp 111:1-8.

Perkins. R.. Fang. H.. Tong. W.. Welsh. W. J. (2003). Quantitative structure-activity relationship methods: Perspectives on drug discovery and toxicology. Environ Toxicol Chem. 22:1666-79.

Keenan. S. M.. Welsh. W. J. (2003). Characterization of the plasmodium falciparum PK5 ATP-binding site: Implications for the design of novel antimalarial agents. J Mol Graph Model 22:241-247.

Ai. N.. DeLisle. RK. Yu. S.. Welsh. W. J. (2003). Computational models for predicting binding affinities of ligands for the wild-type androgen receptor and a mutated variant associated with prostate cancer. Chem. Res. Toxicol 16:1652-1660.

Fang. M Z. Wang. Y. Ai. N. Hou. Z. Sun. Y. Lu. H. Welsh. W J. Yang. C S. (2003). Tea polyphenol (-)-Epigallocatechin-3-Gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Research 63:7563-7570.

Zauhar. R J. Moyna. G. Tian. L. Li. Z. Welsh. W J (2003). Shape signatures: A new approach to computer-aided ligand- and receptor-based drug design. J Med Chem. 6:5674-5690.