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Article ; Online: A perspective on the physicochemical and biopharmaceutic properties of marketed antiseizure drugs-From phenobarbital to cenobamate and beyond.

Odi, Reem / Bibi, David / Wager, Travis / Bialer, Meir

2020 Volume 61, Issue 8, Page(s) 1543–1552

Abstract: The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drug- ... ...

Abstract	The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drug-candidate failure and to capture trends in antiseizure drug (ASD) design, we have analyzed the physicochemical and biopharmaceutical properties of marketed ASDs in comparison with new ASDs in development. Our comparative analysis included molecular weight (MW), logP, polar surface area (PSA), the "Lipinski rule of five," and the CNS Multiparameter Optimization (MPO) score. LogP is the logarithm of a drug-partition coefficient (P) between n-octanol and water. PSA is the molecule's surface sum of its polar atoms. ASDs' biopharmaceutical properties were classified according to their water solubility, permeability, and route of elimination as outlined by the Biopharmaceutics Classification System (BCS) and Biopharmaceutics Drug Disposition Classification System (BDDCS). For old ASDs (1912-1990), logP, PSA, and CNS MPO values ranged between 0.4 and 2.8, 37 and 87 Å
MeSH term(s)	Anticonvulsants/chemistry ; Anticonvulsants/pharmacology ; Chemical Phenomena ; Drug Approval ; Drug Design ; Drug Development ; Humans ; Molecular Weight
Chemical Substances	Anticonvulsants
Language	English
Publishing date	2020-07-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.16597
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Article ; Online: Harnessing Preclinical Data as a Predictive Tool for Human Brain Tissue Targeting.

Patel, Nandini C / Feng, Bo / Hou, Xinjun / West, Mark A / Trapa, Patrick E / Sciabola, Simone / Verhoest, Patrick / Liras, Jennifer L / Maurer, Tristan S / Wager, Travis T

ACS chemical neuroscience

2021 Volume 12, Issue 6, Page(s) 1007–1017

Abstract: One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest ( ...

Abstract	One of the objectives within the medicinal chemistry discipline is to design tissue targeting molecules. The objective of tissue specificity can be either to gain drug access to the compartment of interest (
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Dogs ; Humans ; Madin Darby Canine Kidney Cells ; Neoplasm Proteins/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins
Language	English
Publishing date	2021-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.0c00807
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Article ; Online: Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery.

Wager, Travis T / Hou, Xinjun / Verhoest, Patrick R / Villalobos, Anabella

ACS chemical neuroscience

2016 Volume 7, Issue 6, Page(s) 767–775

Abstract: Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that ... ...

Abstract	Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development.
MeSH term(s)	ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Algorithms ; Animals ; Biological Transport ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Central Nervous System/drug effects ; Central Nervous System/metabolism ; Drug Design ; Humans ; Permeability/drug effects
Chemical Substances	ATP-Binding Cassette, Sub-Family B, Member 1
Language	English
Publishing date	2016--15
Publishing country	United States
Document type	Journal Article
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.6b00029
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Getting the MAX out of Computational Models: The Prediction of Unbound-Brain and Unbound-Plasma Maximum Concentrations.

Mente, Scot / Doran, Angela / Wager, Travis T

ACS medicinal chemistry letters

2012 Volume 3, Issue 6, Page(s) 515–519

Abstract: The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and ... ...

Abstract	The objective of this work was to establish that unbound maximum concentrations may be reasonably predicted from a combination of computed molecular properties assuming subcutaneous (SQ) dosing. Additionally, we show that the maximum unbound plasma and brain concentrations may be projected from a mixture of in vitro absorption, distribution, metabolism, excretion experimental parameters in combination with computed properties (volume of distribution, fraction unbound in microsomes). Finally, we demonstrate the utility of the underlying equations by showing that the maximum total plasma concentrations can be projected from the experimental parameters for a set of compounds with data collected from clinical research.
Language	English
Publishing date	2012-05-16
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/ml300029a
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Article ; Online: Author Correction: Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs.

Ferruz, Noelia / Doerr, Stefan / Vanase-Frawley, Michelle A / Zou, Yaozhong / Chen, Xiaomin / Marr, Eric S / Nelson, Robin T / Kormos, Bethany L / Wager, Travis T / Hou, Xinjun / Villalobos, Anabella / Sciabola, Simone / De Fabritiis, Gianni

Scientific reports

2019 Volume 9, Issue 1, Page(s) 6076

Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. ...

Abstract	A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Language	English
Publishing date	2019-04-10
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-39694-1
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Article ; Online: Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability.

Pettersson, Martin / Hou, Xinjun / Kuhn, Max / Wager, Travis T / Kauffman, Gregory W / Verhoest, Patrick R

Journal of medicinal chemistry

2016 Volume 59, Issue 11, Page(s) 5284–5296

Abstract: Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and ... ...

Abstract	Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.
MeSH term(s)	ATP-Binding Cassette, Sub-Family B, Member 1/chemistry ; ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Fluorine/chemistry ; Fluorine/metabolism ; Hydrophobic and Hydrophilic Interactions ; Molecular Structure ; Molecular Weight ; Permeability
Chemical Substances	ATP-Binding Cassette, Sub-Family B, Member 1 ; Fluorine (284SYP0193)
Language	English
Publishing date	2016-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.6b00027
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Article ; Online: In Vitro-In Vivo Extrapolation of Key Transporter Activity at the Blood-Brain Barrier.

Trapa, Patrick E / Troutman, Matthew D / Lau, Thomas Y / Wager, Travis T / Maurer, Tristan S / Patel, Nandini C / West, Mark A / Umland, John P / Carlo, Anthony A / Feng, Bo / Liras, Jennifer L

Drug metabolism and disposition: the biological fate of chemicals

2019 Volume 47, Issue 4, Page(s) 405–411

Abstract: Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based ...

Abstract	Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based pharmacokinetic model was developed to describe the in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro. In the present work, the predictive utility of this framework was examined through application to in vitro and in vivo data generated on 133 unique compounds across three preclinical species. Two approaches were examined for the scaling of efflux activity to in vivo, namely relative expression as determined by independent proteomics measurements and relative activity as determined via fitting the in vivo neuropharmacokinetic data. The results with both approaches indicate that in vitro efflux data can be used to accurately predict the degree of brain penetration across species within the context of the proposed physiologically based pharmacokinetic framework.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Animals ; Biological Transport/physiology ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Cell Line ; Dogs ; Madin Darby Canine Kidney Cells ; Rats ; Rats, Sprague-Dawley
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1
Language	English
Publishing date	2019-01-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.118.083279
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Article ; Online: Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling.

Wager, Travis T / Liras, Jennifer L / Mente, Scot / Trapa, Patrick

Expert opinion on drug metabolism & toxicology

2012 Volume 8, Issue 5, Page(s) 531–542

Abstract: Introduction: Healthy functioning of the brain is dependent on the ability of the blood-brain barrier (BBB) and other central nervous system (CNS) barriers to protect the neurocompartments from potential disruptive and damaging xenobiotic agents. In ... ...

Abstract	Introduction: Healthy functioning of the brain is dependent on the ability of the blood-brain barrier (BBB) and other central nervous system (CNS) barriers to protect the neurocompartments from potential disruptive and damaging xenobiotic agents. In vitro high-throughput (HT) screens and computational models that assess a compound's ability to pass through or disrupt the BBB have become important tools in the identification of new well-tolerated peripheral drugs and safer chemical products such as pesticides. Leveraging these HT in vitro assays and computational BBB tools together with the current understanding of brain penetration may enable the drug discovery community to minimize access of drug candidates into the CNS compartment. Areas covered: This article reviews aspects of the most recent in vitro and computational approaches designed to provide an early assessment of a compound's ability to access the neurocompartment. This article also provides insight into using these tools to identify compounds that have restricted access to the neurocompartment. Expert opinion: The development of safer peripheral-acting medicines and chemical products can be achieved through prospective design and early assessment with HT assays of the BBB in conjunction with computational models. Exclusion or significantly reduced access of a compound to the neurocompartment will increase the odds of identifying a compound with reduced CNS-related adverse drug reactions. A holistic approach to compound design and evaluation that incorporates prospective design principles (e.g., optimization of physicochemical properties), leverages HT in vitro assays and integrates the use of BBB computational models may yield the 'best-in-class' peripherally acting product.
MeSH term(s)	ATP-Binding Cassette Transporters/metabolism ; Animals ; Blood-Brain Barrier/metabolism ; Central Nervous System/drug effects ; Central Nervous System/pathology ; Chemical Phenomena ; Computer Simulation ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Pharmacokinetics
Language	English
Publishing date	2012-05
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2214462-6
ISSN	1744-7607 ; 1742-5255
ISSN (online)	1744-7607
ISSN	1742-5255
DOI	10.1517/17425255.2012.677028
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Article ; Online: Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs.

Scientific reports

2018 Volume 8, Issue 1, Page(s) 897

Abstract: The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose ... ...

Abstract	The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F
MeSH term(s)	Animals ; Binding Sites/physiology ; Cell Line ; Crystallography, X-Ray/methods ; Humans ; Ligands ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed/methods ; Protein Binding/physiology ; Receptors, Dopamine D3/antagonists & inhibitors ; Receptors, G-Protein-Coupled/chemistry ; Receptors, G-Protein-Coupled/metabolism ; Salicylamides/chemistry ; Salicylamides/metabolism ; Sf9 Cells
Chemical Substances	Ligands ; Receptors, Dopamine D3 ; Receptors, G-Protein-Coupled ; Salicylamides ; eticlopride (J8M468HBH4)
Language	English
Publishing date	2018-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-19345-7
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Article ; Online: Author Correction

Noelia Ferruz / Stefan Doerr / Michelle A. Vanase-Frawley / Yaozhong Zou / Xiaomin Chen / Eric S. Marr / Robin T. Nelson / Bethany L. Kormos / Travis T. Wager / Xinjun Hou / Anabella Villalobos / Simone Sciabola / Gianni De Fabritiis

Scientific Reports, Vol 9, Iss 1, Pp 1-

Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

2019 Volume 4

Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. ...

Abstract	A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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