ABSTRACT
Pharmacophore-based virtual screening (VS) has emerged as an efficient computer-aided drug design technique when appraising multiple ligands with similar structures or targets with unknown crystal structures. Current pharmacophore modeling and analysis software suffers from inadequate integration of mainstream methods and insufficient user-friendly program interface. In this study, we propose a stand-alone, integrated, graphical software for pharmacophore-based VS, termed ePharmer. Both ligand-based and structure-based pharmacophore generation methods were integrated into a compact architecture. Fine-grained modules were carefully organized into the computing, integration, and visualization layers. Graphical design covered the global user interface and specific user operations including editing, evaluation, and task management. Metabolites prediction analysis with the chosen VS result is provided for preselection of wet experiments. Moreover, the underlying computing units largely adopted the preliminary work of our research team. The presented software is currently in client use and will be released for both professional and nonexpert users. Experimental results verified the favorable computing capability, user convenience, and case performance of the proposed software.
Subject(s)
Drug Discovery , Software , Drug Evaluation, Preclinical , Molecular Structure , Structure-Activity RelationshipSubject(s)
Angiotensin II , Myocardial Reperfusion Injury , Humans , Mitochondria , PTEN Phosphohydrolase , Protein KinasesABSTRACT
Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Diabetic Nephropathies/drug therapy , Enzyme Activators/chemistry , Indoles/chemistry , Administration, Oral , Adsorption , Animals , Crystallography, X-Ray , Dogs , Enzyme Activators/chemical synthesis , Enzyme Activators/pharmacokinetics , Enzyme Activators/pharmacology , High-Throughput Screening Assays , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Indazoles/pharmacology , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Injections, Intravenous , Macaca fascicularis , Male , Models, Molecular , Protein Conformation , RatsABSTRACT
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
