Alan C. Rigby, PhD
Assistant Professor of Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-231
Boston, MA 02215
Dr Rigby holds a Honors BSc. in Biochemistry from the University of Western Ontario (1991) and a Ph.D. in Biochemistry (1995) from the same university. Following his Ph.D. Dr Rigby joined the Center for Hemostasis and Thrombosis Research in the laboratory of Dr Bruce Furie. In 1998 Dr Rigby started his independent program as an Instructor of Medicine and was promoted to Assistant Professor of Medicine in 2001. In 2005 Dr Rigby moved his laboratory to the Division of Molecular and Vascular Medicine and became an active member of the Center for Vascular Biology Research.
Structural and Computational Drug Discovery
In order to improve our understanding of the varied interactions that mediate molecular recognition at the cellular and/or structural level, we must clearly understand macromolecular complex assembly from first principles. This approach is only possible through the seamless integration of structural, biophysical and computational approaches that together permit us to characterize and thus understand these complexes at the atomic level. Toward this goal Dr Rigby's laboratory uses heteronuclear NMR spectroscopy, state-of-the-art biophysical and computational approaches to evaluate protein-protein, protein-membrane, protein-ligand and protein-DNA interactions that are requisite for the assembly of complexes critical in blood coagulation, apoptosis, gene regulation and cancer. Using a comprehensive strategy that partners structural and computational approaches Dr Rigby has recently developed novel strategies aimed at targeting a therapeutically important "class" of targets, transcription factors (TFs). His laboratories success in identify small molecules capable of targeting and inhibiting TF-DNA interaction interface for several members of the ETS family of transcription factors has provided a promising paradigm shift in transcriptional therapy, highlighted by the identification of "first in class' compounds.
The Rigby laboratory provides a unique opportunity for scientists with varied expertise's to work synergistically, partnering these innovative approaches to study and better understand the rules and/or principles governing these complex interfaces and the relative energetic contributions bestowed by their inherent architecture.
New and Noteworthy Publications
View all publications via PubMed >>
Morelli XJ, Palma PN, Guerlesquin F,
Rigby AC. (2001) A Novel Approach for Assessing Macromolecular Complexes Combining Soft Docking Calculations with NMR Data. Protein Science 10, p2131.
This paper demonstrated for the first time how rigid body docking calculations partnered with NMR data could be used to reproducibly identify protein-protein complex formation.
Rigby AC*, Morelli XJ, Grant MA, Huang G, Furie B, Seaton B, Furie BC. (2003) Structural Basis of Membrane Binding by Gla Domains of Vitamin K-Dependent Proteins. Nature Structural Biology 10(9), p751. (*co-corresponding author)
This paper addressed a pivotal question in blood coagulation; How do the vitamin K-dependent proteins recognize and assemble on physiologically important membrane surfaces.
Grant MA, Lazo ND, Condron MC,
Rigby AC*, Teplow DB*. (2007) Familial Alzheimer's Disease Mutations Alter the Stability of the Amyloid ?-Protein Monomer Folding Nucleus. Proceedings of the National Academy of Sciences 16, p16522. (*co-corresponding author)
This manuscript identified that familial mutations within Abeta contribute to this loops flexibility, while providing a nucleation point for the onset of toxic clump formation that is ultimately responsible for killing brain cells. Importantly, these data have provided structural and mechanistic details that are being leveraged to discover novel compounds that block this process.
Morelli X.J. and
Rigby AC. Acceleration of the Drug Discovery Process: A Combinatorial Approach Using NMR Spectroscopy and Virtual Screening. (2007). Current Computer-Aided Drug Discovery 3, p33.
This manuscript documents the "discovery" potential of integrating NMR spectroscopy with in silico, virtual screens of large chemical repositories possessing diverse collections of small molecules as an approach for interrogating novel chemical spaces and accelerating hit-through-lead discovery strategies.
Shanmugasundaram K and
Rigby AC. The Exploration of Novel Chemical Space: A Need to Partner Structure-based and Ligand-based In silico Approaches. (2008) Combinatorial Chemistry & High Throughput Screening, In Press.
This manuscript documents an approach for successfully expanding the "druggable space" within the human genome using a systematic approach to search for small molecule leads that selectively target and disrupt this space.