Discovery of Novel HSP27 Inhibitors as Prospective Anti-Cancer Agents Utilizing Computer-Assisted Therapeutic Discovery Approaches

Abstract

Heat shock protein 27 (HSP27) is a protein that works as a chaperone and an antioxidant and is activated by heat shock, environmental stress, and pathophysiological stress. However, HSP27 dysregulation is a characteristic of many human cancers. HSP27 suppresses apoptosis and cytoskeletal reorganization. As a result, it is recognized as a critical therapeutic target for effective cancer therapy. Despite the effectiveness of multiple HSP27 inhibitors in pre-clinical investigations and clinical trials, no HSP27 inhibitor has progressed to the anticancer phase of the development. These difficulties have mostly been attributable to existing anticancer therapies’ inability to target oncogenic HSP27. Highly selective HSP27 inhibitors with higher effective-ness and low toxicity led to the development of combination techniques that include computer-aided assisted therapeutic discovery and design. This study emphasizes the most recent results and roles of HSP27 in cancer and the potential for utilizing an anticancer chemical database to uncover novel compounds to inhibit HSP27.

Deciphering the Lexicon of Protein Targets: A Review on Multifaceted Drug Discovery in the Era of Artificial Intelligence

“…267 This narrative not only paints a progressive picture of HSP27 inhibitor discovery (Figure 4) but it also emphasizes the critical role that computational methodologies play in accelerating the landscape of anticancer drug discovery. 267,271 By fusing theoretical predictions with experimental validations, researchers can get one step closer to developing effective cancer therapeutics. 270,272 Matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, are important in cancer pathology because they degrade the extracellular matrix (ECM), which allows tumor invasion and metastasis.…”

“…By stabilizing the cytoskeleton and facilitating epithelial−mesenchymal transition (EMT), which is vital for metastasis, HSP27 promotes the progression of cancer. 267 Furthermore, it interacts with the extracellular matrix (ECM), which influences cell adhesion and migration, both of which are important steps in cancer invasion. 268 Compound I, one of the notable inhibitors found, shows promise in inhibiting the growth of androgen receptor-overexpressed glioblastoma (AR-overexpressed GBM) cells without causing toxicity to mice by significantly inducing AR degradation in GBM cells via the proteasomal pathway.…”

“…37 Additionally, molecular docking against HSP27 using a computer-assisted therapeutic discovery approach revealed three ligands (BVDU, FR180204, and XAV-939) with similar binding configurations at the target protein site, thereby demonstrating their potential as HSP27 inhibitors. 267 NSC751382, a powerful HSP27 inhibitor, was discovered, which helped overcome the drug resistance problems plaguing many chemotherapeutic drugs. 269 Furthermore, 10 novel compounds were synthesized through a careful design and synthesis study by modifying the pharmacophore of a pyrone ring that is structurally similar to J2 and NA49 at the C2 and/ or C3 positions.…”

“…It is highly expressed in various types of cancers and has been linked to drug resistance. By stabilizing the cytoskeleton and facilitating epithelial–mesenchymal transition (EMT), which is vital for metastasis, HSP27 promotes the progression of cancer . Furthermore, it interacts with the extracellular matrix (ECM), which influences cell adhesion and migration, both of which are important steps in cancer invasion .…”

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“…This method is referred to as the integration of the classical equation of motion. The significance of this might be attributed to the fact that docking provides a fixed representation of a molecule's binding posture in the active site of a protein [15,[17][18][19][20]. Simulations were utilised so that an investigation could be conducted into the physiological condition of the ligand binding process.…”