Taiji Oashi, Ph.D.
Department of Pharmaceutical Sciences,
University of Maryland School of Pharmacy
20 Penn St. HSF2 Rm 601, Baltimore, MD 21201-1075
toashi-at-rx.umaryland.edu
-at- needs to be replaced by @.
410-706-7441

RESEARCH INTERESTS
- Application of supercomputing and statistical mechanics
for the understanding of complex biological phenomena and
drug discovery and development
- Receptor-ligand and protein-protein interactions
- Simulations of biological molecules (DNA, RNA, protein,
lipid, and carbohydrate)


RESEARCH EXPERIENCE and EDUCATION
University of Maryland School of Pharmacy,
Computer-Aided Drug Design Center
Postdoctoral fellow
Advisor: Prof. Alexander D. MacKerell, Jr.
June 2008 - present

Mount Sinai School of Medicine of NYU, Ph.D. in Biophysics (May 2008)
Dissertation:
Computational Biophysical Studies of Peptide-MHC Class II
Interaction in Autoimmunity
Advisor: Profs. Roman Osman, and Yaron Tomer


TECHNICAL EXPERTISE
High Performance Computing in Parallel Environment,
Computer-Aided Drug Design; in silico Docking using over
1.5 million compound database, Lead Identification and
Optimization of Protein Inhibitors Using Target-based,
Fragment-based Drug Design, Similarity Search using ~5 million
compound database, Target Characterization, force field
development of druglike small molecules, Molecular dynamics
(MD) simulation, Targeted MD simulation, Restrained MD
Simulation, Monte Carlo (MC) simulation, Brownian Dynamics
Simulation, Free Energy Calculations (Umbrella Sampling,
MM/PB(GB)SA), Cluster Analysis (ART2, K-mean, Jarvis-Patrick
algorithm), Covariance Analysis, Quasi-harmonic Analysis,
Structural Analysis, Data Fitting, Database Management

- Molecular modeling, and simulation package: CHARMM,
AMBER, NAMD, MMC, MacroDox, Gaussian, Dock, GRASP, Simulaid,
MODELLER, MOE, VMD, Insight II, Discovery Studio, GaussView,
MOLDEN
- Mathematical and statistical package: MATLAB, mathematica,
SPSS, gnuplot
- Platforms: Linux/Unix, SGI/Unix, Mac/Unix, Windows



BRIEF RESERACH DESCRIPTIONS:
I have been working on several projects in computational biophysics, chemoinformatics, biostatistics, method development, and drug discovery and development under the supervision of Profs. Alexander D. MacKerell Jr., Robert J. Bloch, and Paul Shapiro as a post-doctoral researcher in the MacKerell laboratory and Computer-aided Drug Design Center at the University of Maryland School of Pharmacy since June 2008. Profs. Bloch and Shapiro are experimental collaborators who supervised experimental tests of our computational predictions. During the course of these projects, using parallel computing environments, I have done Brownian dynamics (BD) and molecular dynamics (MD) simulations, computer-aided drug design (CADD) including lead identification and optimization of protein inhibitors using target-based, fragment-based, and similarity searching methods as well as force field development of druglike small molecules, data fitting, database management, cluster analysis, covariance analysis, and structural analysis.

Below are brief descriptions of the projects that I have been involved
in the MacKerell laboratory and CADD Center are provided below:
1) ERK2 CADD project
2) Molecular modeling studies of interaction between
sAnk157-122-obsc6322-6339 in striated muscle
3) Automated selection of compounds with physicochemical properties
to maximize bioavailability and druglikeness
4) Notch CADD project
5) Mdmx CADD project




1) ERK2 CADD project
Extracellular signal regulated kinases (ERK1/2) are involved in signaling events that control cell division and proliferation. Hyperactivation of ERK has been implicated in the pathogenesis of many human cancers. The F-site recruitment site (FRS) (L198, H230, Y231, L232, L235, and Y261) as well as common docking (CD) (D316 and D319) and ED (T157 and T158) domain in ERK2 is used to facilitate interactions with substrate proteins. Thus, small molecules targeting FRS and/or CD/ED domain have the potential to modulate ERK2 specific functions, potentially leading to the development of novel therapeutic agents. MD simulations of ERK2 from which structurally diverse conformations were selected were used to identify putative binding sites for low molecular weight compounds in the vicinity of the FRS and CD/ED sites. Identified sites were then targeted in individual database screens of over 1.5 million compounds. Following two levels of database screening, fingerprint based similarity clustering and analysis of physicochemical properties (see 3 below for detail) that maximizes bioavailability, final compounds for biological assay were selected for each site. Inhibition of ERK2-specific phosphorylation was confirmed and dose-dependency was measured in several cancer cell lines using colony survival assays. Direct binding of active compounds to ERK2 was validated by fluorescence quenching experiments. ERK2 was crystallized in complex with several active compounds, showing binding in the critical site in FRS. These identified compounds provide novel tools to study the biological functions of ERK2 as well as act as lead compounds for the development of novel therapeutic candidates for cancer.
In addition to the CADD studies of ERK we performed a series of MD simulations on ERK wildtype and mutants. These studies identified unique structural and dynamical changes in ERK mutants in which autoactivation occurs. Based on the simulations studies, predictions of new mutants that impact ERK activity were made and subsequently validated in experimental studies.

2) Molecular modeling studies of interaction between
sAnk157-122-obsc6322-6339 in striated muscle
Binding of obscurin (obsc) to the muscle-specific small ankyrin1 (sAnk1) is important for organizing the sarcoplasmic reticulum in striated muscle. Experimental work investigating this interaction has been charactering the roles of residues in obsc6322-6339 and sAnk157-122. Molecular modeling methods were used to develop structural models of obsc6322-6339 bound to sAnk157-122 as well as to obtain additional information on this interaction. Initial interaction between obsc6322-6339 and sAnk157-122 was modeled using 10,000 Brownian dynamics simulations followed by the minimization of the complex, with solvation treated using the Generalized-Born method. Obsc is predicted to interact with R67, R68, R69, K101, R104, K105, and R108 in sAnk1, in agreement with experimental results. 30ns MD simulations were then performed on six selected obsc-sAnk1 complexes, two of which were further extended to 70ns. Results show that the alpha helical conformation of obsc is maintained in the complex, where it is stabilized by the interaction with the positively charged binding groove in sAnk1 via electrostatic interactions between specific pairs of side chains on obsc and sAnk1 promote binding and complex formation. Results also show that the binding site on sAnk1 for obscurin is organized as two ankyrin-like repeats, with the last α-helical segment oriented at an angle to the nearby helices, allowing K6338 of obscurin to form an ionic interaction with D111 of sAnk1. These predictions were validated by experiments using charge-switching obsc and sAnk1 mutants. In addition, the modeling provided the dynamic and heterogeneic insights in sAnk157-122-obscurin6322-6339 interaction.

3) Automated selection of compounds with physicochemical
properties to maximize bioavailability and druglikeness
A novel method to select compounds with a combination of physicochemical properties that maximize oral bioavailability and druglikeness was developed based on pharmacologically active compounds in the World Drug Index (WDI) database. In the study four properties, MW, logP(o/w), number of hydrogen bond donors and acceptors were combined into a 4-D histogram, from which a scoring function was defined based on a 4D dependent multivariate normal distribution model. The resulting equation allows for assigning compounds a bioavailability score, termed 4D-BA, such that chemicals with higher 4D-BA scores are more likely to have oral drug-like characteristics. The model was validated by applying the function to drugs previously categorized in the Biopharmaceutics Classification System. The approach is anticipated to be useful in early lead identification studies in combination with clustering methods to maximize chemical and structural diversity when selecting compounds for biological assays from large database screens. It may also be applied to prioritize synthetically feasible chemical modifications during lead compound optimization.

4) Notch CADD project
Notch signaling plays an essential role in regulating cell fate determination and development via transcriptional activation of target genes. Deregulation of Notch signaling has led to the pathogenesis of T cell acute lymphoblastic leukemias, and the formation of neoplasia in skin, breast, and gut. Transcription of Notch target genes are tightly regulated by binding to the transcription factor CSL on cognate DNA followed by the binding of coactivator Mastermind-like-1 (MAML-1) onto the groove composed of Notch and CSL. Thus, small molecular inhibitors targeting CSL interface on Notch have the potential to disrupt Notch-CSL interaction as well as to prevent the formation of Notch-CSL-MAML transcription complex, potentially being developed into the novel therapeutic agents for these diseases. The same database screening protocol as used for ERK2 was applied to identify Notch inhibitors. Two potent active compounds were identified and lead optimization is in progress.

5) Mdmx CADD project
MDM2 and MDMX are oncoproteins that negatively regulate the activity and stability of the tumor suppressor protein p53, where N-terminal p53-binding domain in MDM2 and MDMX is used for binding to transactivation domain in p53, leading to p53 inactivation and tumor survival. Thus, small molecules targeting p53-binding region in MDMX have the potential to disrupt p53-MDMX interaction, resulting in maximizing p53 function and leading to the development of novel anticancer drugs. The same database screening protocol as used for ERK2 was applied to identify MDMX inhibitors. Two active compounds were identified and lead optimization is in progress.


CONFERENCE PRESENTATIONS
- Oashi, T., Zhang, J., Burkhard, K., Priyakumar, U.D.,
Pozharskiy, E., Shapiro, P., and MacKerell, A.D., Jr.
Identification of ERK2-substrate protein inhibitors via virtual
screening, biological assays and X-ray crystallography.
Biophysical Society 55th Annual Meeting (Baltimore, MD, March 2011)
- Oashi, T., Busby, B., Willis, C.D., Bloch, RJ., and
MacKerell, A.D., Jr. Molecular Modeling of Interaction between
sAnk157-122 and obscurin6322-6339 in Striated Muscle. American
Chemical Society Fall Meeting (Washington D.C. 2009)
- Oashi, T., Mezei, M., Kentsis, A., and Osman, R. Bound
Conformation of Peptide Needs To Be Induced by MHC Class II:
MD Study of HLA-DQ8-binding Insulin B (11-24) Peptide Associated
with Type 1 Diabetes. (nominated for Student Research Achievement
Award) Biophysical Society 51st Annual Meeting (Baltimore, MD,
March 2007)
- Oashi, T., Mezei, M., Kentsis, A., and Osman, R. Conformational
Properties of Type 1 Diabetes-inducing Insulin B (11-24) Peptide.
Biophysical Society 48th Annual Meeting
(Baltimore, MD, February 2004)
- Oashi, T., and Osman, R. Structural, Energetic, and Dynamic
Properties of Type 1 Diabetesinducing Insulin B (11-24) Peptide.
Biophysical Society 47th Annual Meeting (San Antonio, TX, March 2003)


PUBLICATIONS (* indicates equal contribution)
Peer-reviewed papers
- Oashi, T., Ringer, A.L., Raman, E.P., and MacKerell, A.D., Jr.
Automated selection of compounds with physicochemical properties
to maximize bioavailability and druglikeness. J. Chem. Inf. Model Accepted
- Barr, D., Oashi, T., Burkhard, K., Lucius, S., Shapiro, P.,
MacKerell, A.D., and van der Vaart, A. The importance of domain
closure for the auto-activation of ERK2. Submitted to J. Mol. Biol.
- Busby, B.*, Oashi, T.*, Willis, C.D., Borzok, M.A., Kontrogianni-
Konstantopouos, A., MacKerell, A.D., Jr., and Bloch, R.J.
Electrostatic Interactions Mediate Binding of Obscurin to Small
Ankyrin 1: Biochemical and Molecular Modeling Studies. Submitted
to J. Mol. Biol.
- Willis, C.D., Busby, B., Oashi, T., MacKerell, A.D., Jr., and
Bloch, R.J. Hydrophobic Interactions Mediate Binding of Obscurin
and Small Ankyrin 1. To be submitted to J. Biol. Chem.
- Oashi, T., Priyakumar, U.D., Nevels, K., Burkhard, K., Smith, S.,
Shapiro, P., and MacKerell, A.D., Jr. Prediction of ATP-independent
inhibitors that target ERK2 on unique substrate docking
domains using computer-aided drug design To be submitted
- Menconi, F., Monti, M.C., Greenberg, D.A., Oashi, T., Osman, R.,
Davies, T.F., Ban, Y., Jacobson, E.M., Concepcion, E.S., Li, C.W.,
and Tomer, Y. Molecular amino acid signatures in the MHC class II
peptide-binding pocket predispose to autoimmune thyroiditis in
humans and in mice. Proc. Natl. Acad. Sci. USA. 105, 14034-14039 (2008)
- Yamoah, K., Oashi, T., Sarikas, A., Gazdoiu, S., Osman, R.,
and Pan, Z.Q. Autoinhibitory regulation of SCF-mediated ubiquitination
by human cullin 1's C-terminal tail. Proc. Natl. Acad. Sci. USA. 105,
12230-12235 (2008)
- Jacobson, E.M., Concepcion, E.S., Oashi, T., and Tomer, Y. A
Graves' disease-associated Kozak sequence single-nucleotide polymorphism
enhances the efficiency of CD40 gene translation: a case for
translational pathophysiology. Endocrinology. 146, 2684-2691 (2005)
- Ban, Y., Davies, T.F., Greenberg, D.A., Concepcion, E.S.,
Osman, R., Oashi, T., and Tomer, Y. Arginine at position 74 of the
HLA-DR Beta1 chain is associated with Graves' disease. Genes
Immun. 5, 203-208 (2004)


Book Chapter
- Zhong, S., Oashi, T., Yu, W., Shapiro, P., and MacKerell, A.D., Jr.
Prospects of modulating protein-protein interactions., In Protein-Ligand
Interactions H. Gohlke ED., Methods and Principles in Medicinal
Chemistry, John Wiley & Sons, Chichester, Submitted.


NVITED SEMINARS
- Computational Biophysical Studies of Peptide-MHC Class II
Interaction in Autoimmunity University of Maryland School of
Pharmacy (January 2008)
Host: Prof. Alexander D. MacKerell, Jr.
- Computational Biophysical Studies of Peptide-MHC Class II
Interaction in Autoimmunity
Massachusetts Institute of Technology (March 2008)
Host: Profs. Martin Karplus and Arup K. Chakraborty


JOURNAL REVIEW
Journal of Physical Chemistry (American Chemical Society)
Journal of Medicinal Chemistry (AmericaiSn Chemical Society)
Journal of Molecular Modeling (Springer)


AWARDS and HONORS
- Travel Award, MSSM (2007)
- Travel Award, MSSM (2003)
- Invited Traineeship in Computational Biology
(Director: Dr. Ken-ichi Matsubara), IIAS (2001)
- MSSM Fellowship (2001-2008)
- Japan Student Services Organization (JASSO) Fellowship (1997-2001)


PROFESSIONAL ACTIVITIES
- Member of the Biophysical Society (2002 - present)
- Member of American Chemical Society (2009 - present)
- Member of New York Academy of Sciences (2003 - present)
- Co-organizer of Mailing List for Japanese Ph.D. Students and
Post-docs in the U.S. and EU (2003-present)
- Hosted Akihiko Konagaya, Ph.D., Professor of Knowledge Science,
JAIST, as a student-invited speaker (2001)
- Hosted Kazuyuki Aihara, Ph.D., Professor of Mathematical
Engineering and Information Physics, University of Tokyo, as a
student-invited speaker (2001)
- Hosted Hidesaburo Hanafusa, Ph.D., Director of Osaka Bioscience
Institute, as a student-invited speaker (2000)
- Hosted Minoru Kanehisa, Ph.D., Professor of ICR, Kyoto University,
as a student-invited speaker (2000)
- Hosted Ikunoshin Kato, Ph.D., Vice President, Takara Shuzo Co., Ltd.
(currently Takara Bio Inc.), as a student-invited speaker (2000)
- Hosted Yasutsugu Shimonishi, Ph.D., Professor and Director of
IPR, Osaka Univ., as a student-invited speaker (2000)


REFERENCES
Alexander D. MacKerell, Jr., Ph.D.
Grollman-Glick Professor of Pharmaceutical Sciences
Director, Computer-Aided Drug Design Center
University of Maryland School of Pharmacy
Tel: 410-706-7442
E-mail: amackere-at-rx.umaryland.edu
-at- needs to be replaced by @.


Roman Osman, Ph.D.
Professor of Structural and Chemical Biology
Mount Sinai School of Medicine of NYU
Tel: 212-659-8627
E-mail: roman.osman-at-mssm.edu


Robert J. Bloch, Ph.D.
Professor of Physiology
University of Maryland School of Medicine
Tel: 410-706-3020
E-mail: rbloch-at-umaryland.edu


Yaron Tomer, MD, FACP
Professor of Medicine
Division of Endocrinology
Vice Chairman of Medicine for Research
Mount Sinai School of Medicine of NYU
Tel: 212-241-6834
E-mail: yaron.tomer-at-mssm.edu


Paul Shapiro, Ph.D.
Associate Professor of Pharmaceutical Sciences
University of Maryland School of Pharmacy
Tel: 410-706-8522
E-mail: pshapiro-at-rx.umaryland.edu


Mihaly Mezei, Ph.D.
Associate Professor of Structural and Chemical Biology
Mount Sinai School of Medicine of NYU
Tel: 212-659-5475
E-mail: Mihaly.Mezei-at-mssm.edu