Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer.
01 Jan 2019-Current Topics in Medicinal Chemistry (Bentham Science Publishers Ltd.)-Vol. 19, Iss: 6, pp 457-466
TL;DR: Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases.
Abstract: Background Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects. Objective In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer. Methods Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs. Results The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges. Conclusion Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.
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TL;DR: Drug repositioning introduces an affordable and efficient strategy to discover novel drug action, especially when integrated with recent systems biology driven stratagem, in combination with conventional anticancer agents to combat drug resistance in the near future.
20 citations
TL;DR: A novel attempt in terms of blending scaffold hopping and hierarchical virtual screening in order to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2).
Abstract: BACKGROUND Though virtual screening methods have proven to be potent in various instances, the technique is practically incomplete to quench the need of drug discovery process. Thus, the quest for novel designing approaches and chemotypes for improved efficacy of lead compounds has been intensified and logistic approaches such as scaffold hopping and hierarchical virtual screening methods were evolved. Till now, in all the previous attempts these two approaches were applied separately. OBJECTIVE In the current work, we made a novel attempt in terms of blending scaffold hopping and hierarchical virtual screening. The prime objective is to assess the hybrid method for its efficacy in identifying active lead molecules for emerging PPI target Bcl-2 (B-cell Lymphoma 2). METHODS We designed novel scaffolds from the reported cores and screened a set of 8270 compounds using both scaffold hopping and hierarchical virtual screening for Bcl-2 protein. Also, we enumerated the libraries using clustering, PAINS filtering, physicochemical characterization and SAR matching. RESULTS We generated a focused library of compounds towards Bcl-2 interface, screened the 8270 compounds and identified top hits for seven families upon fine filtering with PAINS algorithm, features, SAR mapping, synthetic accessibility and similarity search. Our approach retrieved a set of 50 lead compounds. CONCLUSION Finding rational approach meeting the needs of drug discovery process for PPI targets is the need of the hour which can be fulfilled by an extended scaffold hopping approach resulting in focused PPI targeting by providing novel leads with better potency.
5 citations
References
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TL;DR: This review focuses on computational aspects of predicting the best native-like complex structure and binding affinities and provides the latest developments on protein- protein docking and binding affinity studies along with a list of available computational resources for understanding protein-protein interactions.
104 citations
TL;DR: The results suggest that the use of such comprehensive libraries of peptide secondary structure mimetics, built around effective molecular scaffolds, constitutes a powerful method of interrogating PPIs.
Abstract: Transient protein-protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, and immune suppression. The unknown or uncharacterized PPIs involved in such interaction networks often represent compelling therapeutic targets for drug discovery. To date, however, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets. Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such mimetics are available to interrogate PPI targets. We initiated a program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three libraries would be built around templates designed to mimic each such secondary structure and substituted with all triplet combinations of groups representing the 20 natural amino acid side chains. When combined, the three libraries would contain a member capable of mimicking the key interaction and recognition residues of most targetable PPIs. In this Account, we summarize the results of the design, synthesis, and validation of an 8000 member α-helix mimetic library and a 4200 member β-turn mimetic library. We expect that the screening of these libraries will not only provide lead structures against α-helix- or β-turn-mediated protein-protein or peptide-receptor interactions, even if the nature of the interaction is unknown, but also yield key insights into the recognition motif (α-helix or β-turn) and identify the key residues mediating the interaction. Consistent with this expectation, the screening of the libraries against p53/MDM2 and HIV-1 gp41 (α-helix mimetic library) or the opioid receptors (β-turn mimetic library) led to the discovery of library members expected to mimic the known endogenous ligands. These efforts led to the discovery of high-affinity α-helix mimetics (K(i) = 0.7 μM) against HIV-1 gp41 as well as high-affinity and selective β-turn mimetics (K(i) = 80 nM) against the κ-opioid receptor. The results suggest that the use of such comprehensive libraries of peptide secondary structure mimetics, built around effective molecular scaffolds, constitutes a powerful method of interrogating PPIs. These structures provide small molecule modulators of PPI networks for therapeutic target validation, lead compound discovery, and the identification of modulators of biological processes for further study.
95 citations
TL;DR: This review could help medicinal chemists to design novel EGFR TKIs against NSCLC and selectively target T790M mutants, sparing wild-type EGFR.
92 citations
TL;DR: This work describes sequence‐based approaches that use peptides to mimic proteins in order to inhibit the interaction of the mimicked protein with its partners, and discusses a structure‐based approach, in which protein‐peptide complex structures are used to rationally design and optimize peptidic inhibitors.
Abstract: With the decline in productivity of drug-development efforts, novel approaches to rational drug design are being introduced and developed. Naturally occurring and synthetic peptides are emerging as novel promising compounds that can specifically and efficiently modulate signaling pathways in vitro and in vivo. We describe sequence-based approaches that use peptides to mimic proteins in order to inhibit the interaction of the mimicked protein with its partners. We then discuss a structure-based approach, in which protein-peptide complex structures are used to rationally design and optimize peptidic inhibitors. We survey flexible peptide docking techniques and discuss current challenges and future directions in the rational design of peptidic inhibitors.
89 citations
TL;DR: Data provide evidence for the selective killing of tumor cells by YC137 and represent the first example of in vitro selection of cancer cells refractory to a Bcl-2 inhibitor.
Abstract: Proteins of the Bcl-2 family are key regulators of caspase activation and apoptosis. Some members of this family, notably Bcl-2 and Bcl-xL, are overexpressed in cancer cells, which have been associated with chemoresistance. We have designed and synthesized a small molecule inhibitor of Bcl-2, named YC137, and studied its role in cancer cells. In vitro studies showed that YC137 inhibits the binding of the Bid BH3 peptide to Bcl-2, thus disrupting an interaction essential for the antiapoptotic activity of Bcl-2. This inhibitor induces apoptosis of hematopoietic progenitors overexpressing Bcl-2 but not Bcl-xL and breast cancer cells that express high levels of Bcl-2. On the contrary, a variety of normal primary cells, including CD34+ progenitors, myoblasts, and peripheral blood mononuclear cells, do not respond to the inhibitor. A breast cancer cell line resistant to YC137 was generated. Analysis of resistant cells revealed a reduced expression of Bcl-2, which correlated with low activation of signal transducer and activator of transcription-3 (Stat3) and reduced expression of the human epidermal growth factor receptor-2 (HER2). Of note, YC137-resistant cells were more sensitive to apoptosis induced by chemotherapy. Because HER2 has not been linked previously to the Stat3-Bcl-2 transcriptional pathway, we additionally confirmed that specific blockade of HER2 in breast cancer cells resulted in down-regulation of Stat3 activity and reduced levels of Bcl-2. Consistently, HER2 blockade led to YC137 resistance. These data provide evidence for the selective killing of tumor cells by YC137 and represent the first example of in vitro selection of cancer cells refractory to a Bcl-2 inhibitor.
87 citations