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1.
ACS Comb Sci ; 21(2): 75-82, 2019 02 11.
Article in English | MEDLINE | ID: mdl-30672692

ABSTRACT

DNA-encoded chemical libraries (DELs) provide a high-throughput and cost-effective route for screening billions of unique molecules for binding affinity for diverse protein targets. Identifying candidate compounds from these libraries involves affinity selection, DNA sequencing, and measuring enrichment in a sample pool of DNA barcodes. Successful detection of potent binders is affected by many factors, including selection parameters, chemical yields, library amplification, sequencing depth, sequencing errors, library sizes, and the chosen enrichment metric. To date, there has not been a clear consensus about how enrichment from DEL selections should be measured or reported. We propose a normalized  z-score enrichment metric using a binomial distribution model that satisfies important criteria that are relevant for analysis of DEL selection data. The introduced metric is robust with respect to library diversity and sampling and allows for quantitative comparisons of enrichment of n-synthons from parallel DEL selections. These features enable a comparative enrichment analysis strategy that can provide valuable information about hit compounds in early stage drug discovery.


Subject(s)
DNA/chemistry , Small Molecule Libraries/chemistry , Triazines/chemistry , Amines/chemistry , Amino Acids/chemistry , Base Sequence , Combinatorial Chemistry Techniques/methods , Drug Discovery , Epoxide Hydrolases/chemistry
2.
J Chem Inf Model ; 57(7): 1667-1676, 2017 07 24.
Article in English | MEDLINE | ID: mdl-28657313

ABSTRACT

Here we describe the development of novel methods for compound evaluation and prioritization based on the structure-activity relationship matrix (SARM) framework. The SARM data structure allows automatic and exhaustive extraction of SAR patterns from data sets and their organization into a chemically intuitive scaffold/functional-group format. While SARMs have been used in the retrospective analysis of SAR discontinuity and identifying underexplored regions of chemistry space, there have been only a few attempts to apply SARMs prospectively in the prioritization of "close-in" analogs. In this work, three new ways of prioritizing virtual compounds based on SARMs are described: (1) matrix pattern-based prioritization, (2) similarity weighted, matrix pattern-based prioritization, and (3) analysis of variance based prioritization (ANV). All of these methods yielded high predictive power for six benchmark data sets (prediction accuracy R2 range from 0.63 to 0.82), yielding confidence in their application to new design ideas. In particular, the ANV method outperformed the previously reported SARM based method for five out of the six data sets tested. The impact of various SARM parameters were investigated and the reasons why SARM-based compound prioritization methods provide higher predictive power are discussed.


Subject(s)
Drug Discovery/methods , Informatics/methods , Structure-Activity Relationship
3.
ChemMedChem ; 9(7): 1378-86, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24729513

ABSTRACT

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.


Subject(s)
Protease Inhibitors/chemistry , Quinoxalines/chemistry , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Cell Line , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Half-Life , Hepacivirus/metabolism , Humans , Microsomes, Liver/metabolism , Protease Inhibitors/pharmacokinetics , Quinoxalines/chemical synthesis , Quinoxalines/pharmacokinetics , Rats , Structure-Activity Relationship , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacokinetics , Viral Nonstructural Proteins/metabolism
4.
ChemMedChem ; 9(7): 1387-96, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24729518

ABSTRACT

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.


Subject(s)
Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Hepacivirus/metabolism , Humans , Hydrogen Bonding , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
5.
J Med Chem ; 52(21): 6822-34, 2009 Nov 12.
Article in English | MEDLINE | ID: mdl-19821576

ABSTRACT

A series of metal complexes were prepared as potential prodrugs of the extremely toxic DNA minor groove alkylator 1-(chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (seco-6-azaCBI-TMI) and close analogues. The pyrrolo[3,2-f]quinoline cytotoxins were prepared from 2-methoxy-4-nitroaniline in a nine-step synthesis involving a Skraup construction of a quinoline intermediate, its appropriate functionalization, and a final radical cyclization. The metal complexes were prepared from these and the labile metal complex synthons [Co(cyclen)(OTf)(2)](+), [Cr(acac)(2)(H(2)O)(2)](+), and [Co(2)(Me(2)dtc)(5)](+). The cobalt complexes were considerably more stable than the free effectors and showed significant attenuation of the cytotoxicity of the latter, with IC(50) ratios (complex/effector) of 50- to 150-fold, and substantial hypoxic cell selectivity, with IC(50) ratios (oxic/hypoxic cells) of 20- to 40-fold. The cobalt complexes were also efficiently activated by ionizing radiation, with G values for loss of the compound close to the theoretical value for one-electron reduction of 0.68 micromol/J. This work extends earlier observations that cobalt cyclen complexes are suitable for both the bioreductive and radiolytic release of potent pyrrolo[3,2-f]quinoline effectors.


Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , Cobalt , Coordination Complexes/chemical synthesis , Indoles/chemical synthesis , Prodrugs/chemical synthesis , Pyrroles/chemical synthesis , Quinolines/chemical synthesis , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Alkylating/radiation effects , Cell Hypoxia , Cell Line, Tumor , Chelating Agents/chemical synthesis , Chelating Agents/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/radiation effects , Drug Screening Assays, Antitumor , Humans , Indoles/pharmacology , Indoles/radiation effects , Oxidation-Reduction , Prodrugs/pharmacology , Prodrugs/radiation effects , Pyrroles/pharmacology , Pyrroles/radiation effects , Quinolines/pharmacology , Quinolines/radiation effects , Radiation, Ionizing , Stereoisomerism , Structure-Activity Relationship
7.
J Med Chem ; 50(21): 5090-102, 2007 Oct 18.
Article in English | MEDLINE | ID: mdl-17880056

ABSTRACT

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.


Subject(s)
Amides/chemical synthesis , Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Pyridones/chemical synthesis , Amides/chemistry , Amides/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Extracellular Signal-Regulated MAP Kinases/metabolism , MAP Kinase Kinase 1/chemistry , MAP Kinase Kinase 2/chemistry , Male , Mice , Models, Molecular , Neoplasm Transplantation , Phosphorylation , Pyridones/chemistry , Pyridones/pharmacology , Rats , Structure-Activity Relationship
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