# Designing Plk1 Inhibitors through multiscale computational and experimental methods

> **NIH NIH R15** · GALLAUDET UNIVERSITY · 2022 · $368,671

## Abstract

Identification of Novel, Selective Plk1 Inhibitors through Molecular Modeling and
Fluorescence Polarization Experiments
The long-term goal of the proposed study is to identify novel nonpeptide-based selective
inhibitors for polo-box domain (PBD) of polo-like kinase 1 (PLK1) that can be used for targeted
cancer therapies. Given its major role in mitotic events, PLK1 is a marker for cellular proliferation
with a prognostic potential in some types of cancers. A high level of PLK1 expression is associated
with a poor prognosis. Studies have shown that the loss of PLK1 expression can induce apoptosis
and inhibit growth in many cancer cells while showing an insignificant effect on normal cells in
mouse models. On the other hand, PLK2 and PLK3 have been identified as tumor suppressors.
Therefore, selective and specific inhibition of PLK1 is a promising therapeutic strategy for a range
of cancer types. In our study, the rationale for targeting the PBD as opposed to the kinase
catalytic domain (KCD) is that the KCD is conserved among kinases and therefore poses
selectivity and toxicity problems. PLK1 inhibitors will be identified in several steps. (1) Small
molecules with known binding profiles to PLK1-3 will be studied through molecular dynamics (MD)
simulations to gain atomistic insights for the key interactions needed for strong binding profile for
PLK1 but not for PLK2-3. (2) COCONUT natural products database and Atomwise company small
molecule database will be screened to identify potential inhibitors. The top hit candidates will be
studies through MD and ADMETS (absorption, distribution, metabolism, excretion, toxicity and
stability) simulations to reduce the number of candidates and finally the top molecules will be
studies through steered MD and fluorescence polarization experiments. The proposed study is
innovative in many aspects but particularly its unique design for allowing meaningful participation
of Deaf and Hard of Hearing undergraduate and high school students. Major outcome of the
study is that it is expected to provide a starting point for a drug design pipeline for the PBD of
PLK1 and further guide the in vivo experiments and/or clinical considerations.

## Key facts

- **NIH application ID:** 10580435
- **Project number:** 1R15GM148942-01
- **Recipient organization:** GALLAUDET UNIVERSITY
- **Principal Investigator:** Tugba Kucukkal
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,671
- **Award type:** 1
- **Project period:** 2022-09-20 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10580435

## Citation

> US National Institutes of Health, RePORTER application 10580435, Designing Plk1 Inhibitors through multiscale computational and experimental methods (1R15GM148942-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10580435. Licensed CC0.

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