Dr. Tiwari's research utilizes both computational approaches such as molecular docking, virtual screening, and molecular dynamics (MD) simulations and experimental techniques such as surface plasmon resonance (SPR) biophysical and other biochemical experiments. Dr. Tiwari is also collaborating with researchers at Georgetown University (GU) and other institutions outside of GU. Dr. Tiwari's research activities are primarily focused on following topics:
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Drug Development:
DNA Topoisomerases as targets: DNA topoisomerase (topo) regulates DNA topology, which has special importance in key cellular processes, including replication, transcription, and recombination. Human topoisomerase I (HtopoI) forms a transient covalent complex with DNA and is a druggable target for novel topoisomerase poison inhibitors that represent a new class of anticancer drugs.
Human topos (Htopos) and other enzymes that have a functional relationship with Htopos can also be used as drug targets for the development of anticancer drugs. Dr. Tiwari's current research is focused on targeting these important biomolecules to discover new small molecule (SM) inhibitors that can be developed as anticancer agents. Bacterial DNA topoI forms a transient covalent complex with DNA and can be a druggable target for novel topoI poison inhibitors that represent a new class of antibacterial drugs. Besides Htopos and related targets, Dr. Tiwari's current research is focused on finding new SM inhibitors targeting EctopoI that can be developed as new antibacterial drugs to treat bacterial infections.
HtopoI-DNA covalent complex.
Complex formation between E. coli topoisomerase I (EctopoI) and RNA polymerase.
TDP1 and PARP1 as targets: Tyrosyl-phosphodiesterase 1 (TDP1) catalyzes the hydrolysis of the phosphodiester bond between an active site tyrosine in HtopoI and DNA 3’-phosphate making TDP1 functionally connected with HtopoI activity. TDP1 interacts with Poly [ADP-ribose] polymerase 1 (PARP1) and gets PARylated that enhances recruitment of TDP1 to DNA damage sites. Dr. Tiwari's research involves development of new inhibitors targeting these two functionally important proteins.
TDP1-PARP1 binding interface
TDP1-PARP1 binding
MEF2s as targets: Myocyte enhancer factor 2 (MEF2) transcription factors regulate various developmental programs. Class IIa HDACs physically interact with MEF2s to repress MEF2-associated gene expression. Dr. Tiwari's research has interest in targeting MEF2s and blocking interactions of class IIa HDACs MEF2s towards development of novel therapeutics (click here for more details).
Structure of predicted HDAC4-MEF2A complex (left) and SPR-based experimental validation of the HDAC4-MEF2A complex formation (right). Click here for more details.
Biophysical Characterizations:
DNA Topoisomerases and their binding partners: Dr. Tiwari's research has interest in the biophysical characterization of complex formation between topos and their binding partners.
HDACs and their binding partners: Dr. Tiwari's is also interested in characterization of complex formations of HDACs with other binding partners, including other HDACs and MEF2s (Click here: All class IIa-MEF2s complexes (except the HDAC7-MEF2A complex), HDAC7-MEF2A complex)
Heme proteins: Dr. Tiwari is also interested in biophysical characterization of complex formation between heme proteins, including Neuroglobin (Ngb) and Cytochrome c (Cyt c). Neuroglobin (Ngb) is a six-coordinated heme protein and Cytochrome c (Cyt c) is another heme protein, a known binding partner of Ngb. The formation of a complex between Ngb and Cyt c has an important biological role in preventing apoptosis.
Kaiso binding proteins: Dr. Tiwari is also involved in collaborative research to characterize interactions of Kaiso binding proteins with their binding partners.
Methods/Models/Tools Development:
Besides interest in drug development and characterization of biomolecular interactions, Dr. Tiwari is interested in developing new methods/models/tools to investigate and analyze the biomolecular interactions.
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