Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking

Abstract

Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel–Lindau interaction.

The Effectiveness of Combined Drug Delivery Systems

“…To build a self-assembly structure, camptothecin is conjugated with short oligo ethylene glycol. This can enable the patient to overcome drug resistance [9][10][11][12][13] . Similar to these conjugates, the nanoparticles that originate from the polymer self-assembly are highly effective.…”

“…Curcumin is yet another polyphenol that engages in anticancer activity and also down regulates the pathways from functioning and progressing the cancer cells further to other parts. It is observed that the co-delivery has a higher potential to control MDR and this only requires the proper selection of the nanotherapeutic delivery system to choose inhibitor/ sensitizer/ modulator [9][10][11]37 .…”

Peptide Conjugated Lipid Nanoparticles for Anti-Cancer Drug Delivery

“…Sun et al analyzed the effects of using peptide ligand structures for Doxorubicin DOX drug delivery in the case of breast cancer treatment and lymphoma treatment [8][9][10][11][12][13][14] . Traditionally, although DOX was effective for breast cancer treatment, the cardiotoxicity concerns necessitated the research into finding more suitable alternatives for drug delivery.…”

“…Thus, in the context of cancer, anti-angiogenesis refers to the inhibition of the formation of those new vessels that make the cancer cells thrive. The researchers used a drug delivery system DDS where the nanoparticles conjugated with the peptides [6][7][8][9][10][11][12][13] . The size of the conjugated nanoparticles made it easier for those particles to be assimilated and internalized within the human umbilical vein and expected antiangiogenic activity occurred.…”

Peptide-based Drug Delivery for Curing Cancer

“…The first section of this review details about the assembly of peptides while the next part discusses more on the influence of peptide-based ligand on the health of the patient. Peptides quickly turn into proteins and can penetrate to the top layer of the patient's skin thereby having a long-term impact of the medicine [6][7][8][9][10][11] . The final part of this report discusses how peptides can serve as better drug delivery mechanism leaving a significant development in the health aspect of the person.…”