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
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TL;DR: The discovery of epigenetic targets has accelerated to the point where more than 400 domains have been identified that are involved in either DNA methylation, the modification of histones (and some nonhistones), or translation of these modifications into changes in gene expression.
Abstract: Epigenetic control of gene expression occurs at two distinct levels: DNA methylation and histone modification. Over the past 10 years, the discovery of epigenetic targets has accelerated to the point where more than 400 domains have been identified that are involved in either DNA methylation, the modification of histones (and some nonhistones), or translation of these modifications into changes in gene expression.
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27 citations
TL;DR: Analysis of molecular dynamics simulations and PCA analysis on wild-type and mutant structures indicate stability loss and increased flexibility in the mutant structure which results in structural changes which render the mutant protein drug resistant against erlotinib.
Abstract: The epidermal growth factor receptor (EGFR) is a member of the ErbB family that is involved in a number of processes responsible for cancer development and progression such as angiogenesis, apoptosis, cell proliferation and metastatic spread. Malfunction in activation of protein tyrosine kinases has been shown to result in uncontrolled cell growth. The EGFR TK domain has been identified as suitable target in cancer therapy and tyrosine kinase inhibitors such as erlotinib have been used for treatment of cancer. Mutations in the region of the EGFR gene encoding the tyrosine kinase (TK) domain causes altered responses to EGFR TK inhibitors (TKI). In this paper we perform molecular dynamics simulations and PCA analysis on wild-type and mutant (T854A) structures to gain insight into the structural changes observed in the target protein upon mutation. We also report two novel inhibitors identified by combined approach of QSAR model development. The wild-type and mutant structure was observed to be stable for 26 ns and 24 ns respectively. In PCA analysis, the mutant structure proved to be more flexible than wild-type. We developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds which was later used for prediction of inhibitory activity of natural compounds of ZINC library. The 3D-QSAR model was proved to be robust by the statistical parameters such as r2 (0.9751), q2(0.9491) and pred_r2(0.9525). Analysis of molecular dynamics simulations results indicate stability loss and increased flexibility in the mutant structure. This flexibility results in structural changes which render the mutant protein drug resistant against erlotinib. We report two novel compounds having high predicted inhibitory activity to EGFR TK domain with both wild-type and mutant structure.
26 citations
TL;DR: It is confirmed that ASP103 of Bcl-2 is a key residue and that hydrogen bonding between ASP103 and ABT-199 confers the BCl-2 selectivity of this inhibitor, and that for B cl-XL selectivity, the secondary structure of α-helix 3 is akey factor.
Abstract: B-cell lymphoma 2 (Bcl-2) family proteins are potential drug targets in cancer and have a relatively flat and flexible binding site. ABT-199 is one of the most promising selective Bcl-2 inhibitors, and A-1155463 selectively inhibits Bcl-XL. Although the amino acid sequences of the binding sites of these two inhibitors are similar, the inhibitors selectively bind the target protein. In order to determine the origin of the selectivity of these inhibitors, we conducted molecular dynamics simulations using protein-inhibitor modeling. We confirmed that ASP103 of Bcl-2 is a key residue and that hydrogen bonding between ASP103 and ABT-199 confers the Bcl-2 selectivity of this inhibitor. For Bcl-XL selectivity, the secondary structure of α-helix 3 is a key factor. PHE105, SER106, and LEU108 in the loose α-helix 3 interact with A-1155463 to confer Bcl-XL selectivity. These findings provide important insights into the molecular mechanisms of selective inhibitors of Bcl-2 family proteins.
25 citations
TL;DR: One of these, transforming acidic coiled-coil proteins (TACC) 3, stabilizes EGFR on the cell surface, which results in an increase in downstream signaling via the mitogen-activated protein kinase and AKT pathway, suggesting that targeting TACC3 has potential as a new therapeutic approach for non-small cell lung cancer.
23 citations
TL;DR: In this article, the authors identified 2-(3-((4,6-dioxo-2,thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahedrobenzo[b]thiophene-3-carbonitrile as an MDM2-p53 inhibitor (IC50 = 12.3 μM).
Abstract: Screening identified 2-(3-((4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl)-2,5-dimethyl-1H-pyrrol-1-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile as an MDM2–p53 inhibitor (IC50 = 12.3 μM). MDM2–p53 and MDMX–p53 activity was seen for 5-((1-(4-chlorophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (MDM2 IC50 = 0.11 μM; MDMX IC50 = 4.2 μM) and 5-((1-(4-nitrophenyl)-2,5-diphenyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (MDM2 IC50 = 0.15 μM; MDMX IC50 = 4.2 μM), and cellular activity consistent with p53 activation in MDM2 amplified cells. Further SAR studies demonstrated the requirement for the triarylpyrrole moiety for MDMX–p53 activity but not for MDM2–p53 inhibition.
23 citations