Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir

Abstract

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

“…It is likely that identification of Nelfinavir's cellular targets will help define the mechanisms controlling CReP levels and phosphatase complex activity. If this mechanism is probably complex and may rely on binding to multiple targets (16), the common biological properties shared by the HIV-PIs may also reflect their common specific chemical properties. Most HIV-PIs are peptidomimetics that were designed based on a synthetic analog of the peptide bond between phenylalanine and proline at positions 167 and 168 of the gag-pol polyprotein, a target of the HIV protease (43).…”

“…This is particularly true for molecules such as Nelfinavir that may interact with multiple off-targets (16). Beyond understanding the off-target effects of the drugs, the study of these molecular mechanisms provides an opportunity to identify cellular pathways of biological relevance.…”

Pharmacological eEF 2K activation promotes cell death and inhibits cancer progression

“…Recently, we found that NFR is a robust inducer of the integrated stress response (ISR), an adaptation response that promotes an ATF4-dependant transcriptional program [17]. While some of these pathways may contribute to its antitumoral activity, none has been demonstrated to be essential and the molecular basis of NFR-mediated anti-tumoral effects remains unknown [16,18,19].…”

Natural compounds for the drug targets of Sexually Transmitted Diseases (STD) using virtual screening

“…The functional groups modify the electronic properties of the targets; as a result they have the potential to block the metabolic pathway or restraint the conformation. Different methods have been used to predict the drug targets interaction based on QSAR [18], reverse docking [19], [20], [21]. The interactions can also be interpreted by, side effect similarity, drug based similarity, and target based similarity, based on interpretation of the networks [22], [23].…”