We are currently developing methods that will speed the course of discovery.

• Shape Signatures Tool
• Novel Strategy for Therapeutic Treatment of Amyloid Diseases
• “Docking & Scoring” Scheme for Virtual Drug Screening
• Computational Tools for Analysis and Interpretation of Microarray Data

Shape Signatures Tool

Together with Dr. Randy Zauhar (USIP, Phila, PA), we have developed (patent pending) a novel computational tool for drug discovery known as “Shape Signatures” that rapidly matches small drug–like molecules against each other or against receptor pockets based on similarity in shape and electrostatic properties.

Shape Signatures: A New Approach to Computer-Aided Ligand- and Receptor-Based Drug Design, R J Zauhar, G Moyna, L Tian, Z Li, W J Welsh, J Med Chem. 46, 5674-5690 (2003)

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Novel Strategy for Therapeutic Treatment of Amyloid Diseases

Amyloid fibril formation is associated with many lethal diseases including Alzheimer’s disease, Parkinson’s disease, and Type II diabetes. Our laboratory has developed (patent pending) a computational tool that identifies those sequences within proteins or polypeptides which are especially susceptible to amyloid fibril formation. We call this susceptibility “hidden ?-strand propensity”, since it refers to the strong propensity for specific sequences to transform from their native helical or coil secondary structure to ?-strands under certain physiologically relevant conditions. We are now applying this predictive tool to guide the design and synthesis of novel therapeutic agents useful for the prevention and treatment of amyloid diseases. (Top)

“Docking & Scoring” Scheme for Virtual Drug Screening

We have recently developed (patent pending) a novel scheme for docking & scoring, a computational technique widely used in drug discovery for virtual screening of large small-molecule databases against known protein targets. Our technique, named OSKAR, represents an innovative strategy to achieving a balance between speed and accuracy.

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

Identification of a Minimal Subset of Receptor Conformations for Improved Multiple Conformation Docking and Two-Step Scoring, S. Yoon, W. J. Welsh, J Chem. Inf. Comput. Sci., 44(1):88-96 (2004).

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Computational Tools for Analysis and Interpretation of Microarray Data

DNA microarray technology has led to an explosion of gene expression data. However, virtually every experiment contains missing entries arising from blemishes on the microarray, and values of missing entries must be estimated before clustering can be applied. Our laboratory has recently co-developed (patent pending) a missing value estimation method based on Gaussian mixture modeling. Our estimation method has been shown empirically to be more accurate than existing methods.

Gaussian mixture clustering and imputation of microarray data, M Ouyang, WJ Welsh, and P Georgopoulos, Bioinformatics, Epub ahead of print (2004)

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