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William M. Atkins - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Promiscuity Among Drug Metabolizing Enzymes and Drug Transporters
The FEBS journal, 2019Co-Authors: William M. AtkinsAbstract:Detoxication, or 'drug-metabolizing', enzymes and drug transporters exhibit remarkable substrate Promiscuity and catalytic Promiscuity. In contrast to substrate-specific enzymes that participate in defined metabolic pathways, individual detoxication enzymes must cope with substrates of vast structural diversity, including previously unencountered environmental toxins. Presumably, evolution selects for a balance of 'adequate' kcat /KM values for a wide range of substrates, rather than optimizing kcat /KM for any individual substrate. However, the structural, energetic, and metabolic properties that achieve this balance, and hence optimize detoxication, are not well understood. Two features of detoxication enzymes that are frequently cited as contributions to Promiscuity include the exploitation of highly reactive versatile cofactors, or cosubstrates, and a high degree of flexibility within the protein structure. This review examines these intuitive mechanisms in detail and clarifies the contributions of the classic ligand binding models 'induced fit' (IF) and 'conformational selection' (CS) to substrate Promiscuity. The available literature data for drug metabolizing enzymes and transporters suggest that IF is exploited by these promiscuous detoxication enzymes, as it is with substrate-specific enzymes, but the detoxication enzymes uniquely exploit 'IFs' to retain a wide range of substrates at their active sites. In contrast, whereas CS provides no catalytic advantage to substrate-specific enzymes, promiscuous enzymes may uniquely exploit it to recruit a wide range of substrates. The combination of CS and IF, for recruitment and retention of substrates, can potentially optimize the Promiscuity of drug metabolizing enzymes and drug transporters.
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enzymatic detoxication conformational selection and the role of molten globule active sites
Journal of Biological Chemistry, 2013Co-Authors: Matthew T Honaker, Bengt Mannervik, William M. Atkins, Mauro Acchione, Wei ZhangAbstract:The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning “induced fit” versus “conformational selection” has, however, ignored detoxication enzymes, which exhibit catalytic Promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1–1 (GSTA1–1), exploits a molten globule-like active site to achieve remarkable catalytic Promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic Promiscuity is used to compare engineered variants of GSTA1–1 and the catalytic Promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that “local” molten globule behavior optimizes detoxication enzymes.
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ensemble perspective for catalytic Promiscuity calorimetric analysis of the active site conformational landscape of a detoxification enzyme
Journal of Biological Chemistry, 2011Co-Authors: Matthew T Honaker, Mauro Acchione, John P Sumida, William M. AtkinsAbstract:Enzymological paradigms have shifted recently to acknowledge the biological importance of catalytic Promiscuity. However, catalytic Promiscuity is a poorly understood property, and no thermodynamic treatment has described the conformational landscape of promiscuous versus substrate-specific enzymes. Here, two structurally similar glutathione transferase (GST, glutathione S-transferase) isoforms with high specificity or high Promiscuity are compared. Differential scanning calorimetry (DSC) indicates a reversible low temperature transition for the promiscuous GSTA1-1 that is not observed with substrate-specific GSTA4-4. This transition is assigned to rearrangement of the C terminus at the active site of GSTA1-1 based on the effects of ligands and mutations. Near-UV and far-UV circular dichroism indicate that this transition is due to repacking of tertiary contacts with the remainder of the subunit, rather than “unfolding” of the C terminus per se. Analysis of the DSC data using a modified Landau theory indicates that the local conformational landscape of the active site of GSTA1-1 is smooth, with barrierless transitions between states. The partition function of the C-terminal states is a broad unimodal distribution at all temperatures within this DSC transition. In contrast, the remainder of the GSTA1-1 subunit and the GSTA4-4 protein exhibit folded and unfolded macrostates with a significant energy barrier separating them. Their partition function includes a sharp unimodal distribution of states only at temperatures that yield either folded or unfolded macrostates. At intermediate temperatures the partition function includes a bimodal distribution. The barrierless rearrangement of the GSTA1-1 active site within a local smooth energy landscape suggests a thermodynamic basis for catalytic Promiscuity.
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Quantifying and predicting the Promiscuity and isoform specificity of small-molecule cytochrome P450 inhibitors.
Drug metabolism and disposition: the biological fate of chemicals, 2010Co-Authors: Abhinav Nath, Michael Zientek, Benjamin J. Burke, Ying Jiang, William M. AtkinsAbstract:Drug Promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug Promiscuity are handicapped by the lack of a good way of quantifying Promiscuity. In this article, we present a new entropy-based index of drug Promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by small-molecule drugs and drug candidates, and we demonstrate how drug Promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and Promiscuity of small molecules, using a set of fingerprint-based descriptors.
Klaus R Liedl - One of the best experts on this subject based on the ideXlab platform.
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characterizing the diversity of the cdr h3 loop conformational ensembles in relationship to antibody binding properties
Frontiers in Immunology, 2019Co-Authors: Monica L Fernandezquintero, Johannes R Loeffler, Johannes Kraml, Ursula Kahler, Anna S Kamenik, Klaus R LiedlAbstract:We present an approach to assess antibody CDR-H3 loops according to their dynamic properties using molecular dynamics simulations. We selected six antibodies in three pairs differing substantially in their individual Promiscuity respectively specificity. For two pairs of antibodies crystal structures are available in different states of maturation and used as starting structures for the analyses. For a third pair we chose two antibody CDR sequences obtained from a synthetic library and predicted the respective structures. For all three pairs of antibodies we performed metadynamics simulations to overcome the limitations in conformational sampling imposed by high energy barriers. Additionally, we used classic molecular dynamics simulations to describe nano- to microsecond flexibility and to estimate up to millisecond kinetics of captured conformational transitions. The methodology represents the antibodies as conformational ensembles and allows comprehensive analysis of structural diversity, thermodynamics of conformations and kinetics of structural transitions. Referring to the concept of conformational selection we investigated the link between Promiscuity and flexibility of the antibodies' binding interfaces. The obtained detailed characterization of the binding interface clearly indicates a link between structural flexibility and binding Promiscuity for this set of antibodies.
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Data_Sheet_1_Characterizing the Diversity of the CDR-H3 Loop Conformational Ensembles in Relationship to Antibody Binding Properties.docx
2019Co-Authors: Monica L. Fernández-quintero, Johannes R Loeffler, Johannes Kraml, Ursula Kahler, Anna S Kamenik, Klaus R LiedlAbstract:We present an approach to assess antibody CDR-H3 loops according to their dynamic properties using molecular dynamics simulations. We selected six antibodies in three pairs differing substantially in their individual Promiscuity respectively specificity. For two pairs of antibodies crystal structures are available in different states of maturation and used as starting structures for the analyses. For a third pair we chose two antibody CDR sequences obtained from a synthetic library and predicted the respective structures. For all three pairs of antibodies we performed metadynamics simulations to overcome the limitations in conformational sampling imposed by high energy barriers. Additionally, we used classic molecular dynamics simulations to describe nano- to microsecond flexibility and to estimate up to millisecond kinetics of captured conformational transitions. The methodology represents the antibodies as conformational ensembles and allows comprehensive analysis of structural diversity, thermodynamics of conformations and kinetics of structural transitions. Referring to the concept of conformational selection we investigated the link between Promiscuity and flexibility of the antibodies' binding interfaces. The obtained detailed characterization of the binding interface clearly indicates a link between structural flexibility and binding Promiscuity for this set of antibodies.
Jürgen Bajorath - One of the best experts on this subject based on the ideXlab platform.
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entering the big data era in medicinal chemistry molecular Promiscuity analysis revisited
Future Science OA, 2017Co-Authors: Jürgen BajorathAbstract:The ‘big data’ concept plays an increasingly important role in many scientific fields. Big data involves more than unprecedentedly large volumes of data that become available. Different criteria characterizing big data must be carefully considered in computational data mining, as we discuss herein focusing on medicinal chemistry. This is a scientific discipline where big data is beginning to emerge and provide new opportunities. For example, the ability of many drugs to specifically interact with multiple targets, termed Promiscuity, forms the molecular basis of polypharmacology, a hot topic in drug discovery. Compound Promiscuity analysis is an area that is much influenced by big data phenomena. Different results are obtained depending on chosen data selection and confidence criteria, as we also demonstrate.
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identification and analysis of Promiscuity cliffs formed by bioactive compounds and experimental implications
RSC Advances, 2017Co-Authors: Dilyana Dimova, Erik Gilberg, Jürgen BajorathAbstract:Multi-target activities of small molecules must be distinguished from apparent Promiscuity resulting from assay artifacts. The molecular origins of specific multi-target activities are currently poorly understood. Compounds from the medicinal chemistry literature with available high-confidence activity data were systematically searched for ‘Promiscuity cliffs’, defined as pairs of structural analogs with large differences between the number of targets they are active against. During the search, compounds with detectable aggregator properties, pan-assay interference characteristics, or other possible chemical liabilities were eliminated. A large number of Promiscuity cliffs remained, many of which were centered on a limited number of highly promiscuous compounds, as revealed by network representations. The analysis of Promiscuity cliffs often suggested follow-up experiments to further explore the molecular basis of Promiscuity and assess the influence of data sparseness. Therefore, Promiscuity cliffs identified herein are made freely available to support follow-up investigations.
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Determining the Degree of Promiscuity of Extensively Assayed Compounds.
PloS one, 2016Co-Authors: Swarit Jasial, Jürgen BajorathAbstract:In the context of polypharmacology, an emerging concept in drug discovery, Promiscuity is rationalized as the ability of compounds to specifically interact with multiple targets. Promiscuity of drugs and bioactive compounds has thus far been analyzed computationally on the basis of activity annotations, without taking assay frequencies or inactivity records into account. Most recent estimates have indicated that bioactive compounds interact on average with only one to two targets, whereas drugs interact with six or more. In this study, we have further extended Promiscuity analysis by identifying the most extensively assayed public domain compounds and systematically determining their Promiscuity. These compounds were tested in hundreds of assays against hundreds of targets. In our analysis, assay Promiscuity was distinguished from target Promiscuity and separately analyzed for primary and confirmatory assays. Differences between the degree of assay and target Promiscuity were surprisingly small and average and median degrees of target Promiscuity of 2.6 to 3.4 and 2.0 were determined, respectively. Thus, target Promiscuity remained at a low level even for most extensively tested active compounds. These findings provide further evidence that bioactive compounds are less promiscuous than drugs and have implications for pharmaceutical research. In addition to a possible explanation that drugs are more extensively tested for additional targets, the results would also support a "Promiscuity enrichment model" according to which promiscuous compounds might be preferentially selected for therapeutic efficacy during clinical evaluation to ultimately become drugs.
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What is the Likelihood of an Active Compound to Be Promiscuous? Systematic Assessment of Compound Promiscuity on the Basis of PubChem Confirmatory Bioassay Data
The AAPS journal, 2013Co-Authors: Jürgen BajorathAbstract:Compound Promiscuity refers to the ability of small molecules to specifically interact with multiple targets, which represents the origin of polypharmacology. Promiscuity is thought to be a widespread characteristic of pharmaceutically relevant compounds. Yet, the degree of Promiscuity among active compounds from different sources remains uncertain. Here, we report a thorough analysis of compound Promiscuity on the basis of more than 1,000 PubChem confirmatory bioassays, which yields an upper-limit assessment of Promiscuity among active compounds. Because most PubChem compounds have been tested in large numbers of assays, data sparseness has not been a limiting factor for the current analysis. We have determined that there is an overall likelihood of ∼50% of an active PubChem compound to interact with two or more targets. The probability to interact with more than five targets is reduced to 7.6%. On average, an active PubChem compound was found to interact with ∼2.5 targets. Moreover, if only activities consistently detected in all assays available for a given target were considered, this ratio was further reduced to ∼2.3 targets per compound. For comparison, we have also analyzed high-confidence activity data from ChEMBL, the major public repository of compounds from medicinal chemistry, and determined that an active ChEMBL compound interacted on average with only ∼1.5 targets. Taken together, our results indicate that the degree of compound Promiscuity is lower than often assumed.
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Compound Promiscuity: what can we learn from current data?
Drug discovery today, 2013Co-Authors: Jürgen BajorathAbstract:The specificity paradigm that assigns central relevance to achieving target specificity of drug candidates has recently been revisited. Evidence is mounting that polypharmacological drug behavior is often responsible for therapeutic efficacy suggesting the consideration of new drug development strategies. Target Promiscuity of compounds is at the origin of polypharmacology. For many bioactive compounds, multiple target annotations are available indicating that compound Promiscuity is a general phenomenon. However, careful analysis of compound activity data reveals that the degree of apparent Promiscuity is strongly influenced by data selection criteria and the type of activity measurements that are considered. Furthermore, Promiscuity involving unrelated targets is less common. Apparent target Promiscuity might often better be interpreted as activity Promiscuity in different assays.
Monica L Fernandezquintero - One of the best experts on this subject based on the ideXlab platform.
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characterizing the diversity of the cdr h3 loop conformational ensembles in relationship to antibody binding properties
Frontiers in Immunology, 2019Co-Authors: Monica L Fernandezquintero, Johannes R Loeffler, Johannes Kraml, Ursula Kahler, Anna S Kamenik, Klaus R LiedlAbstract:We present an approach to assess antibody CDR-H3 loops according to their dynamic properties using molecular dynamics simulations. We selected six antibodies in three pairs differing substantially in their individual Promiscuity respectively specificity. For two pairs of antibodies crystal structures are available in different states of maturation and used as starting structures for the analyses. For a third pair we chose two antibody CDR sequences obtained from a synthetic library and predicted the respective structures. For all three pairs of antibodies we performed metadynamics simulations to overcome the limitations in conformational sampling imposed by high energy barriers. Additionally, we used classic molecular dynamics simulations to describe nano- to microsecond flexibility and to estimate up to millisecond kinetics of captured conformational transitions. The methodology represents the antibodies as conformational ensembles and allows comprehensive analysis of structural diversity, thermodynamics of conformations and kinetics of structural transitions. Referring to the concept of conformational selection we investigated the link between Promiscuity and flexibility of the antibodies' binding interfaces. The obtained detailed characterization of the binding interface clearly indicates a link between structural flexibility and binding Promiscuity for this set of antibodies.
Matthew T Honaker - One of the best experts on this subject based on the ideXlab platform.
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enzymatic detoxication conformational selection and the role of molten globule active sites
Journal of Biological Chemistry, 2013Co-Authors: Matthew T Honaker, Bengt Mannervik, William M. Atkins, Mauro Acchione, Wei ZhangAbstract:The role of conformational ensembles in enzymatic reactions remains unclear. Discussion concerning “induced fit” versus “conformational selection” has, however, ignored detoxication enzymes, which exhibit catalytic Promiscuity. These enzymes dominate drug metabolism and determine drug-drug interactions. The detoxication enzyme glutathione transferase A1–1 (GSTA1–1), exploits a molten globule-like active site to achieve remarkable catalytic Promiscuity wherein the substrate-free conformational ensemble is broad with barrierless transitions between states. A quantitative index of catalytic Promiscuity is used to compare engineered variants of GSTA1–1 and the catalytic Promiscuity correlates strongly with characteristics of the thermodynamic partition function, for the substrate-free enzymes. Access to chemically disparate transition states is encoded by the substrate-free conformational ensemble. Pre-steady state catalytic data confirm an extension of the conformational selection model, wherein different substrates select different starting conformations. The kinetic liability of the conformational breadth is minimized by a smooth landscape. We propose that “local” molten globule behavior optimizes detoxication enzymes.
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ensemble perspective for catalytic Promiscuity calorimetric analysis of the active site conformational landscape of a detoxification enzyme
Journal of Biological Chemistry, 2011Co-Authors: Matthew T Honaker, Mauro Acchione, John P Sumida, William M. AtkinsAbstract:Enzymological paradigms have shifted recently to acknowledge the biological importance of catalytic Promiscuity. However, catalytic Promiscuity is a poorly understood property, and no thermodynamic treatment has described the conformational landscape of promiscuous versus substrate-specific enzymes. Here, two structurally similar glutathione transferase (GST, glutathione S-transferase) isoforms with high specificity or high Promiscuity are compared. Differential scanning calorimetry (DSC) indicates a reversible low temperature transition for the promiscuous GSTA1-1 that is not observed with substrate-specific GSTA4-4. This transition is assigned to rearrangement of the C terminus at the active site of GSTA1-1 based on the effects of ligands and mutations. Near-UV and far-UV circular dichroism indicate that this transition is due to repacking of tertiary contacts with the remainder of the subunit, rather than “unfolding” of the C terminus per se. Analysis of the DSC data using a modified Landau theory indicates that the local conformational landscape of the active site of GSTA1-1 is smooth, with barrierless transitions between states. The partition function of the C-terminal states is a broad unimodal distribution at all temperatures within this DSC transition. In contrast, the remainder of the GSTA1-1 subunit and the GSTA4-4 protein exhibit folded and unfolded macrostates with a significant energy barrier separating them. Their partition function includes a sharp unimodal distribution of states only at temperatures that yield either folded or unfolded macrostates. At intermediate temperatures the partition function includes a bimodal distribution. The barrierless rearrangement of the GSTA1-1 active site within a local smooth energy landscape suggests a thermodynamic basis for catalytic Promiscuity.
