Heat Shock Protein 90 (HSP90) Inhibitors as Anticancer Medicines: A Review on the Computer-Aided Drug Discovery Approaches over the Past Five Years

Abstract

Cancer is a disease caused by the uncontrolled, abnormal growth of cells in different anatomic sites. In 2018, it was predicted that the worldwide cancer burden would rise to 18.1 million new cases and 9.6 million deaths. Anticancer compounds, often known as chemotherapeutic medicines, have gained much interest in recent cancer research. These medicines work through various biological processes in targeting cells at various stages of the cell’s life cycle. One of the most significant roadblocks to developing anticancer drugs is that traditional chemotherapy affects normal cells and cancer cells, resulting in substantial side effects. Recently, advancements in new drug development methodologies and the prediction of the targeted interatomic and intermolecular ligand interaction sites have been beneficial. This has prompted further research into developing and discovering novel chemical species as preferred therapeutic compounds against specific cancer types. Identifying new drug molecules with high selectivity and specificity for cancer is a prerequisite in the treatment and management of the disease. The overexpression of HSP90 occurs in patients with cancer, and the HSP90 triggers unstable harmful kinase functions, which enhance carcinogenesis. Therefore, the development of potent HSP90 inhibitors with high selectivity and specificity becomes very imperative. The activities of HSP90 as chaperones and cochaperones are complex due to the conformational dynamism, and this could be one of the reasons why no HSP90 drugs have made it beyond the clinical trials. Nevertheless, HSP90 modulations appear to be preferred due to the competitive inhibition of the targeted N-terminal adenosine triphosphate pocket. This study, therefore, presents an overview of the various computational models implored in the development of HSP90 inhibitors as anticancer medicines. We hereby suggest an extensive investigation of advanced computational modelling of the three different domains of HSP90 for potent, effective inhibitor design with minimal off-target effects.

CUL-6/cullin ubiquitin ligase-mediated degradation of HSP-90 by intestinal lysosomes promotes thermotolerance

“…Numerous drugs inhibit HSP-90, such as those developed to treat cancer that lead to degradation of oncogenic kinase clients of HSP-90. 48 Thus, if the pathway we have identified for degradation of HSP-90 itself in C. elegans is conserved in humans, our findings may have relevance for efficacy of those drugs. Several studies in C. elegans have now shown that reduction of protein quality control factors can paradoxically promote organismal survival.…”

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

“…Furthermore, it formed a hydrophilic interaction through a water bridge with ASN51. Asn51 was discovered to be an essential residue to interact stably with Hsp90, as reported by Magwenyane [ 51 ]. The hydrophobic interactions were noticed with ALA111, LEU107, LEU103, VAL150, TYR139, PHE138, TRP162, VAL136, VAL186, MET98, ILE96, ALA55, and LEU48 residues ( Figure 6 A and 7A).…”

Emerging Promise of Computational Techniques in Anti-Cancer Research: At a Glance

“…Most of the time, scoring abilities can be separated into learning-based and observation-based categories. The latter employ a variety of (frequently physically inspired) terms whose coefficients are advanced using a specific informational index with known binding free energies, in contrast to the former, which use a reversal of the Boltzmann factor to compute scores from the repetition of various perceptions [ 55 , 58 , 59 ].…”