Research Areas

Dr. Welsh’s laboratory specializes in the development and application of computational tools for pharmaceutical drug discovery, predictive toxicology, and multi-dimensional pattern recognition. His laboratory’s interests extend to the molecular design and modeling of synthetic polymers, protein-material interactions, and protein-ligand interactions. In recent years, his laboratory has participated in the discovery of potential drug candidates for the treatment cancer, severe and chronic pain, and infectious diseases.

Research Highlights

Implemented the Shape Signatures tool for applications relevant to computational toxicology; major accomplishments achieved include:

1. Development of shape-based regression and classification models to predict inhibitors of acetylcholine esterase;
2. Development of shape-based classification models to predict ligands to the human Ether-a-go-go gene (hERG) and the humanhydroxytryptophan 2b (5HT2b) receptor, both of which are associated with cardiotoxicity;
3. Development of shape-based classification models to predict ligand blood-brain barrier (BBB) permeability, which is a prerequisite for CNS activity

Employed molecular modeling approaches to delineate and visualize how human ADA3 regulates the transcriptional activity of RAR(alpha) through direct interaction between LxxLL motifs and the receptor coactivator pocket.
Developed shape-based prioritization and classification approaches to predict human pregnane x receptor activators.
Identified and characterized a binding site for small-molecule PXR antagonists that interact on the outer surface of PXR at the AF-2 domain; major accomplishments achieved include:

1. Development of a pharmacophore that describes the structural requirements for these PXR antagonists
2. Computational prediction, and in vitro confirmation, of several low-micromolar PXR antagonists that target this binding site at the AF-2 domain.
3. Development of a three-dimensional structural model of the PXR.2, the major human PXR splice variant that demonstrates reduced ligand-activated transcriptional activation compared with the wild-type PXR.1.

Using microarray techniques to characterize gene expression profiles predictive of monomethylarsonous acid (MMA(III)) exposure and mode of action of carcinogenesis, we observed increases in transcript abundance of Fosl1, Myc, and Rac1 oncogenes in mouse skin. The results support previous findings of the inducibility of these oncogenes in response to arsenic and support the relevance of these genomic changes in skin tumor induction in the K6/ODC mouse model.

Scholarly Activities

• Served as an external consultant for the US EPA in preparing instructional materials for the agency’s training program “New Developments in Computational Methods for Risk Assessment” (Sept-Dec 2010).
• Presented seminar on the topic “Computational Models for Risk Assessment” at the Molecular Operating Environment (MOE) software workshop, located in Monmouth Junction, NJ (October 2010).
• Presented invited seminar entitled “Chemometric Models to Discriminate USP-grade Heparin from Impure and Contaminated Heparin” at the American Association of Pharmaceutical Scientists meeting in New Orleans, LA (November 15, 2010).
• Presented invited seminar entitled “Novel Designs of Autophagy Inhibitors as Anticancer Drugs” at the UMDNJ-RWJMS Cancer Institute of New Jersey (November 29, 2010).
• Presented invited seminar at the U.S. Army Telemedicine and Advanced Technology Research Center (TATRC) Program Review at the Center for Biomaterials Research, Rutgers University, on December 15, 2010.
• Contributed a talk entitled “Computational Approaches to Accelerate the Discovery of Medical Countermeasures Against Select Agents” at the US DoD Defense Threat Reduction Agency (DTRA) Program Review held in College Station TX on January 10-13, 2011.
• Presented an invited seminar entitled “Rational Computer-Aided Design of Drugs to Combat Biowarfare Agents” at the New York Center for Structural Biology in New York City on January 21, 2011.
• Presented an invited seminar entitled “Accelerating Drug Discovery” at the University of Cincinnati Medical Center, Cincinnati OH on February 22, 2011.
• Presented an invited seminar entitled “Novel Computational Approaches to Accelerate Drug Discovery” at Kean University in New Jersey on March 2, 2011.

Recent Publication

1. Zhang, VY, O’Connor, SL, Welsh, WJ, James, MH. Machine learning models to predict ligand binding affinity for the orexin 1 receptor. Artif Intell Chem. 2024;2 (1):. doi: 10.1016/j.aichem.2023.100040. PubMed PMID:38476266 PubMed Central PMC10927255
2. Knowles, LG, Armanious, AJ, Peng, Y, Welsh, WJ, James, MH. Recent advances in drug discovery efforts targeting the sigma 1 receptor system: Implications for novel medications designed to reduce excessive drug and food seeking. Addict Neurosci. 2023;8 :. doi: 10.1016/j.addicn.2023.100126. PubMed PMID:37753198 PubMed Central PMC10519676
3. Yu, Y, Dong, H, Peng, Y, Welsh, WJ. QSAR-Based Computational Approaches to Accelerate the Discovery of Sigma-2 Receptor (S2R) Ligands as Therapeutic Drugs. Molecules. 2021;26 (17):. doi: 10.3390/molecules26175270. PubMed PMID:34500703 PubMed Central PMC8434483
4. Peng, Y, Zhang, Q, Welsh, WJ. Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management. J Med Chem. 2021;64 (1):890-904. doi: 10.1021/acs.jmedchem.0c01964. PubMed PMID:33372782
5. Peng, Y, Zhang, Q, Zielinski, RM, Howells, RD, Welsh, WJ. Identification of an irreversible PPARγ antagonist with potent anticancer activity. Pharmacol Res Perspect. 2020;8 (6):e00693. doi: 10.1002/prp2.693. PubMed PMID:33280279 PubMed Central PMC7719157
6. Peng, Y, Dong, H, Welsh, WJ. Comprehensive 3D-QSAR Model Predicts Binding Affinity of Structurally Diverse Sigma 1 Receptor Ligands. J Chem Inf Model. 2019;59 (1):486-497. doi: 10.1021/acs.jcim.8b00521. PubMed PMID:30497261
7. Kang, JS, Zhang, AL, Faheem, M, Zhang, CJ, Ai, N, Buynak, JD, Welsh, WJ, Oelschlaeger, P. Virtual Screening and Experimental Testing of B1 Metallo-β-lactamase Inhibitors. J Chem Inf Model. 2018;58 (9):1902-1914. doi: 10.1021/acs.jcim.8b00133. PubMed PMID:30107123 PubMed Central PMC6527342
8. Kimani, SG, Kumar, S, Bansal, N, Singh, K, Kholodovych, V, Comollo, T, Peng, Y, Kotenko, SV, Sarafianos, SG, Bertino, JR et al.. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity. Sci Rep. 2017;7 :43908. doi: 10.1038/srep43908. PubMed PMID:28272423 PubMed Central PMC5341070
9. Ai, N, Wood, RD, Yang, E, Welsh, WJ. Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain. Pharm Res. 2016;33 (12):3044-3056. doi: 10.1007/s11095-016-2027-9. PubMed PMID:27631130
10. Groen, N, Guvendiren, M, Rabitz, H, Welsh, WJ, Kohn, J, de Boer, J. Stepping into the omics era: Opportunities and challenges for biomaterials science and engineering. Acta Biomater. 2016;34 :133-142. doi: 10.1016/j.actbio.2016.02.015. PubMed PMID:26876875 PubMed Central PMC4830461

After completing his Ph.D. in chemistry at the University of Chicago, Dr. Weschler did postdoctoral studies with Prof. Fred Basolo at Northwestern University. In 1975 he joined Bell Laboratories as a research scientist in the Physical Chemistry Division. He conducted research at Bell Labs and its successor institutions until 2001 being named a Distinguished Member of Technical Staff (1986). In 2001 he retired from Bellcore/Telcordia and accepted positions at the Environmental & Occupational Health Science Institute and the International Centre for Indoor Environment and Energy, Technical University of Denmark. He has continued in those positions through the present. In 2010 he joined the faculty of the Building Science department at Tsinghua University (Beijing) as an ongoing Visiting Professor. He is also an Adjunct Professor in the Rutgers School of Public Health. He was a Member of the Committee on Air Quality in Passenger Cabins in Commercial Aircraft, National Academy of Sciences, 2000-2001; Advisor on Strategies to Protect the Health of Deployed US Forces, National Academy of Sciences, 1998-2000; Member of the Committee to Review the Structure and Performance of the Health Effects Institute, National Academy of Sciences, 1991-1993; and Member of the Committee on Advances in Assessing Human Exposure to Airborne Pollutants, National Academy of Sciences, 1987-1990. From 1999-2005 he served on the US EPA’s Science Advisory Board. He was elected to the International Academy of Indoor Air Sciences in 1999 and received the Pettenkofer Award, its highest honor, in 2014. He has been conferred the 2017 Haagen-Smit Prize from Atmospheric Environment; “Distinguished Visiting Professor” at Tsinghua University (2018); “Doctor Technices Honoris Causa” from the Technical University of Denmark (2018); and was recently (2020) elected a Fellow of the American Association for the Advancement of Science (AAAS). He has an h-index of 75 with over 19,000 citations (Web of Science) and 86 with over 27,000 citations (Google Scholar).

Chemical reactions among indoor pollutants; their products, including free radicals and secondary organic aerosols. Gas/particle and gas/surface partitioning in indoor environments. Factors that influence the concentrations, transport and surface accumulations of indoor pollutants. Indoor pollutant exposures; their contributions to total pollutant exposures and consequent health effects. Uptake of organic pollutants via dermal absorption

Research Highlights

• Identified phthalates, organophosphates and cyclic siloxanes in indoor airborne particles (early ’80s).
• Identified certain reactions catalyzed by transition metals as sources of free radicals within aqueous atmospheric aerosols (mid ’80’s).
• Early assessment of indoor ozone exposures showing that they are often comparable to or larger than outdoor exposures (late ’80s).
• Demonstrated substantive impact of ozone-initiated chemistry on indoor environments (early ’90s).
• Outlined circumstantial evidence for meaningful levels of nitrate radicals indoors (early ’90s).
• Predicted, and later confirmed, significant indoor levels of hydroxyl radicals from ozone/terpene reactions (mid 90s).
• Called out broad influence of indoor chemistry and suggesting areas for future research; follow-up reviews at 7-yr intervals (mid ’90s).
• Identified ozone/terpene chemistry as a strong indoor source of secondary organic aerosols (late ’90s).
• Recognized the potential adverse health effects of ozone reaction products indoors (mid ’00s).
• Critically reviewed indoor pollutants, primary & secondary, resulting from the use of cleaning agents and air fresheners indoors (mid ’00s).
• Discovered the importance of ozone/skin oil chemistry as a sink for ozone and a source of oxygenated organics in occupied environments (late ’00s).
• Cataloged the changing nature of the chemicals found indoors over the past 50 years (late ’00s).
• Presented a physical-chemistry based framework for better understanding of SVOC dynamics in indoor environments (late ’00s).
• Demonstrated that city-to-city differences in indoor exposures to outdoor ozone partially explain city-to-city variability in short-term mortality coefficients associated with ozone; similarly for PM10 (early ’10s).
• Identified dermal absorption, directly from air, as a significant exposure pathway for certain indoor organic pollutants (early ’10s).

Scholarly Activities

• Visiting Professor (ongoing), International Centre for Indoor Environment and Energy, Technical University of Denmark, 2001 – present.
• Visiting Professor & Distinguished Visiting Professor, Building Sciences, Tsinghua University (Beijing), 2010 – present.
• Editorial advisory boards: Indoor Air: 2007-present; Atmospheric Environment: 2003-2014
• Indoor Air Associate Editor, 2001-2007
• Co-PI in the Air Transportation Center of Excellence for Airliner Cabin Environment Research (ACER) sponsored by U.S. FAA, 2004 – 2014.
• Served on four committees for the National Academy of Sciences, the U.S. EPA’s Science Advisory Board and NIOSH’s NORA committee. Former Chair of the Science Advisory Board for an NSF Center at University of Texas, Austin.
• Guest Professor: University of Innsbruck, Austria (2004, 2006 — 2009); University of Kuopio, Finland (2004); University of Umea, Sweden (2003)

Publications

Click here for a full list of Dr. Weschler’s Publications

1. Langer, S, Weschler, CJ, Bekö, G, Morrison, G, Sjöblom, A, Giovanoulis, G, Wargocki, P, Wang, N, Zannoni, N, Yang, S et al.. Squalene Depletion in Skin Following Human Exposure to Ozone under Controlled Chamber Conditions. Environ Sci Technol. 2024;58 (15):6693-6703. doi: 10.1021/acs.est.3c09394. PubMed PMID:38577981
2. Weschler, CJ, Nazaroff, WW. Ozone Loss: A Surrogate for the Indoor Concentration of Ozone-Derived Products. Environ Sci Technol. 2023;57 (36):13569-13578. doi: 10.1021/acs.est.3c03968. PubMed PMID:37639667
3. Qu, Y, Zou, Z, Weschler, CJ, Liu, Y, Yang, X. Quantifying Ozone-Dependent Emissions of Volatile Organic Compounds from the Human Body. Environ Sci Technol. 2023;57 (35):13104-13113. doi: 10.1021/acs.est.3c02340. PubMed PMID:37610659
4. He, L, Weschler, CJ, Zhang, Y, Li, F, Bergin, MH, Black, M, Zhang, JJ. Ozone Reaction Products Associated with Biomarkers of Cardiorespiratory Pathophysiology. Am J Respir Crit Care Med. 2023;207 (9):1243-1246. doi: 10.1164/rccm.202212-2203LE. PubMed PMID:36701642 PubMed Central PMC10161747
5. Zannoni, N, Lakey, PSJ, Won, Y, Shiraiwa, M, Rim, D, Weschler, CJ, Wang, N, Ernle, L, Li, M, Bekö, G et al.. The human oxidation field. Science. 2022;377 (6610):1071-1077. doi: 10.1126/science.abn0340. PubMed PMID:36048928
6. Abbatt, JPD, Morrison, GC, Grassian, VH, Shiraiwa, M, Weschler, CJ, Ziemann, PJ. How should we define an indoor surface?. Indoor Air. 2022;32 (1):e12955. doi: 10.1111/ina.12955. PubMed PMID:35104002
7. Yang, S, Licina, D, Weschler, CJ, Wang, N, Zannoni, N, Li, M, Vanhanen, J, Langer, S, Wargocki, P, Williams, J et al.. Ozone Initiates Human-Derived Emission of Nanocluster Aerosols. Environ Sci Technol. 2021;55 (21):14536-14545. doi: 10.1021/acs.est.1c03379. PubMed PMID:34672572
8. Nazaroff, WW, Weschler, CJ. Indoor ozone: Concentrations and influencing factors. Indoor Air. 2022;32 (1):e12942. doi: 10.1111/ina.12942. PubMed PMID:34609012
9. Zannoni, N, Li, M, Wang, N, Ernle, L, Bekö, G, Wargocki, P, Langer, S, Weschler, CJ, Morrison, G, Williams, J et al.. Effect of Ozone, Clothing, Temperature, and Humidity on the Total OH Reactivity Emitted from Humans. Environ Sci Technol. 2021;55 (20):13614-13624. doi: 10.1021/acs.est.1c01831. PubMed PMID:34591444 PubMed Central PMC8529706
10. Liu, Y, Misztal, PK, Arata, C, Weschler, CJ, Nazaroff, WW, Goldstein, AH. Observing ozone chemistry in an occupied residence. Proc Natl Acad Sci U S A. 2021;118 (6):. doi: 10.1073/pnas.2018140118. PubMed PMID:33526680 PubMed Central PMC8017968