Automated chemical hypothesis generation and database searching with Catalyst®

A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemicalfeature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r ) 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC 50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.

show abstract

“…30 At the end of the run, Catalyst produced 10 hypotheses. The top-ranked one, Outhypo-38969.22 (Hypo1 for simplicity), is shown in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

“…30 Molecular structures are treated as templates consisting of strategically positioned chemical functions that will bind effectively with complementary functions on receptors. Conformational flexibility is modeled by creating multiple conformers, which are treated simultaneously during the runs.…”

Section: Methodsmentioning

confidence: 99%

Simple but Highly Effective Three-Dimensional Chemical-Feature-Based Pharmacophore Model for Diketo Acid Derivatives as Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors

et al. 2005

View full text Add to dashboard Cite

show abstract

“…In this study, we used the HypoGen program [34] in Accelrys Discovery studio 2.1 to generate PhModels. At the initial step, 3D conformations of the training set inhibitors were generated by using "3D-QSAR Pharmacophore Generation protocol" with the BEST generating algorithm and based on the CHARMm-like force field.…”

Section: Pharmacophore Generationmentioning

confidence: 99%

3D-QSAR Study for Checkpoint Kinase 2 Inhibitors through Pharmacophore Hypotheses

Wang¹,

Lin²,

Shih³

et al. 2013

IJCEA

View full text Add to dashboard Cite

Abstract-DNA-damage is induced by ionizing radiation, genotoxic chemicals or collapsed replication forks. To prevent and repair the DNA-damage, mammalian cells will control and stabilize the genome by cell cycle checkpoint. Checkpoint kinase 2 (Chk2) is one of the important kinases that has a great effect on DNA-damage and plays an important role in response to DNA double-strand breaks and related lesions. Hence, in this study, we will concentrate on Chk2 and the purpose is to build the pharmacophore hypotheses (PhModels) by 3D-QSAR study which can identify inhibitors with high biological activities. Ten PhModels were generated by the HypoGen Best algorithm. The established PhModel, Hypo01, was evaluated in the cost function analysis of its correlation coefficient (r), RMS, cost difference, and configuration cost, with the values: 0.955, 1.28, 192.51, and 16.07, respectively. The result of Fischer's cross-validation test for Hypo01 model yielded a 95% confidence level, and the correlation coefficient (r test ) of the testing set yielded a best value of 0.81.

show abstract

“…The pharmacophores with common features were generated using the HipHop algorithm. 17 Predefined pharmacophore features were used to automatically create the pharmacophore hypothesis model. The list of features of the minimum and maximum values was as follows: H-bond acceptor (Hba) 0 and 5, H-bond donor (Hbd) 0 and 5, Hydrophobic (Hy) 0 and 5.…”

Section: Synthesis Of 5-methoxy-3-(phenylethynyl-2-(2-pyridine-2-yl) mentioning

confidence: 99%

A Novel 3-Phenylethynyl-2-yl-oxy Quinoxaline Core Skeleton and Pharmacophore Model as a Hypoxia-inducible Factor Inhibitor

Gong¹,

Kang²

2010

Bulletin of the Korean Chemical Society

View full text Add to dashboard Cite

The hypoxia-inducible factor (HIF) is a transcription factor induced by hypoxia that is degraded by ubiquitin-dependent proteasomes in normoxic conditions. HIF-1α regulates the transcription of many genes involved in key aspects of cancer biology, including various immortalizations, maintenance of stem cell pools, cellular dedifferentiation, genetic instability, vascularization, metabolic reprogramming, autocrine growth factor signaling, invasion/metastasis, and treatment failure.1 As hypoxic tumor cells are resistant to conventional chemotherapy and radio-therapy, their presence exacerbates patient prognosis. 2-4The importance of HIF-1α in the mediation of normal and pathological processes has motivated considerable efforts to identify HIF-1α inhibitors. Although a wealth of inhibitory compounds is available, synthesizing HIF-1α inhibitors with a novel small-molecule core skeleton fitting individual HIF-1α has proven to be a challenge. Many reports have described the development of anticancer agents targeting HIF-1α, but only a few anticancer agents, incorporating heterocyclic rings and several aromatic core skeletons, have been identified as inhibitors of HIF-1α. [5][6] We therefore attempted to develop novel and simple, drug-like, heterocyclic derivatives as inhibitors of HIF-1α.7 By using the bioisostere concept based on benzene ring-fused, bicyclic HIF-1α inhibitors, we designed scaffolds that combine the pyridine moiety found in the 3-phenylethynyl-2-yl-oxy quinoxaline ring system. 8 Herein, we report initial evidence showing that compounds with a 3-phenylethynyl-2-yl-oxy quinoxaline core skeleton are selective HIF-1α inhibitors, and therefore have potential to be anticancer agents. The aim of this study was to investigate the biochemical properties of HIF-1α and identify new core skeleton inhibitors of HIF-1α. To identify such small-molecule inhibitors of HIF-1α, we screened 163 substituted quinoxaline derivatives using the HRE/SW480 stable cell line containing HRE-luc[pHTS-9XHRE-Luc]. Once HIF-1α was induced, the hypoxia response element (HRE) promoter was activated by binding with HIF-1α, which in turn activated the reporter gene, luciferase. Therefore, the compounds can be tested for whether HIF-1α activation is inhibited using this system. The 163 screened quinoxaline compounds represent 4,000 structurally diverse and druggable derivatives. 9-11The efficacy of the 163 compounds in inhibiting Hif-RGA cell proliferation was screened at a compound concentration of 5 μM and the compounds that reproducibly inhibited growth by over 80% were selected. In the first round of screening, 18 compounds reproducibly exhibited an IC 50 value below 2.5 μM. We found structural similarity for the 3-position of the substituted phenylethynyl group and the 2-position of yl-oxy group on the quinoxaline as hit compounds of HIF-1α cell activities. Among them, the 2 hit compounds selected for further screening had the following structures: 6-amino-3-substituted phenylethynyl-2-yl-oxy quinoxaline (Figure 1, compound 3892) and ...

show abstract

Automated chemical hypothesis generation and database searching with Catalyst®

Cited by 125 publications

References 25 publications

Simple but Highly Effective Three-Dimensional Chemical-Feature-Based Pharmacophore Model for Diketo Acid Derivatives as Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors

Simple but Highly Effective Three-Dimensional Chemical-Feature-Based Pharmacophore Model for Diketo Acid Derivatives as Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors

3D-QSAR Study for Checkpoint Kinase 2 Inhibitors through Pharmacophore Hypotheses

A Novel 3-Phenylethynyl-2-yl-oxy Quinoxaline Core Skeleton and Pharmacophore Model as a Hypoxia-inducible Factor Inhibitor

Contact Info

Product

Resources

About