HSP90 inhibitors(Hansoh Pharmaceuticals)

The N-terminal Hsp90 inhibitors are promising targets for cancer treatment; however, inducing the heat shock response is one of the most significant limitations. A prominent way to overcome this limitation is by inhibiting the Hsp90 C-terminal domain.

In this study, a set of structure-based methods was engaged to predict the new C-terminal inhibitors. Since there was no human PDB structure of the Hsp90 C-terminal domain, homology modeling was done using the SWISS-MODEL server online. The 3D structure of the model was refined through energy minimization using molecular dynamics (MD) simulation for 10 ns. The active site of the created model was validated by novobiocin docking. Four steps of virtual screening, including HTVS, SP, XP, and QM/MM docking, were performed on the created library (151,332 compounds) based on 80% similarity to deguelin as the C-terminal inhibitor. The best-obtained compounds were introduced to MM-GBSA studies. Finally, the stability of the best compound was investigated using a 100 ns MD simulation.

Four steps of virtual screening were performed on the created library. The extracted 46 compounds with the XP GlideScore of < -4.164 kcal/mol were introduced to MM-GBSA studies, and rescoring was done. The stability of compound CID_14018348, the best compound (ΔG binding = -80.45 kcal/mol), was investigated using MD simulation.

The compound CID_14018348 was identified as the most promising candidate through computational techniques; therefore, the computational methods outlined can be applied in the development of potent anticancer agents.

The causative agent of malaria, Plasmodium falciparum, encodes four heat shock protein 90 isoforms in the cytosol, endoplasmic reticulum, mitochondria and apicoplast. PfHsp90s are considered potential targets for developing antimalarial drugs. However, the similarity between the druggable ATP binding pocket of these isoforms and their human counterparts has hindered efforts in discovering Hsp90-based antimalarial drugs. There is widespread concern that the chemotypes targeting PfHsp90 isoforms may not possess the selectivity required for translatability. Most studies have focused on the cytosolic (canonical Hsp90) and have used various inhibitors of Hsp90 to conduct anti-Plasmodium and mammalian safety studies without considering the on-target enzymatic activity and binding affinity. The extent to which the cytosolic Hsp90 shares common mechanisms with the other isoforms remains elusive. As such, detailed structural comparisons of the Hsp90 isoforms may reveal exploitable differences that could favour preferential binding. It is essential to consider whether molecules that act as pan-inhibitors would put more pressure on the parasite or have detrimental effects. Studies should go beyond molecular docking and whole-cell activity to advance the development of Hsp90 inhibitors as future antimalarials. There is a need also to assess the physicochemical properties, drug metabolism, pharmacokinetics, and In vivo proof-of-concept. We argue that the potential benefits of PfHsp90 isoform inhibitors outweigh the off-target and selectivity risks. Additionally, opportunities for using machine learning and computer-aided drug discovery efforts to design inhibitors that preferentially bind to each isoform, particularly the cytosolic PfHsp90, are highlighted as a means of overcoming the resistance challenge.