Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [ 3 H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26°C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal ⅐ mol Ϫ1 ), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (⌬H O ) and entropy (ϪT⌬S O )contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% ⌬G O ) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.Inhibitors of the serotonin transporter (SERT) have long been in clinical use for treatment of depression and anxiety, predating even the molecular identification of the target (Blakely et al., 1991). As such, SERT is the target of a large number of clinically proven drugs from diverse chemotypes (Fig. 1) that act by blocking transit of 5-hydroytryptamine (serotonin) (5-HT) through the transporter. Many reports describe the equilibrium binding properties of members of this class of drugs with SERT as well as potency for inhibition of 5-HT reuptake (Blakely et al., 1994;Tatsumi et al., 1997;Nemeroff and Owens, 2003;Rothman and Baumann, 2003). Although the three-dimensional structure of SERT has not yet been elucidated, crystal structures have been determined for other members of the 12 transmembrane domain major facilitator superfamily. Of these, the most homologous transporter to SERT is the bacterial leucine transporter LeuT (Yamashita et al., 2005). A three-dimensional model of SERT based on the published crystal structure of LeuT places several key amino acid residues that interact with SERT inhibitors along the proposed substrate permeation path (Ravna et al., 2006a).Recently, crystal structures of LeuT in complex with highaffinity SERT inhibitors wer...
Considering their shared mechanism of action, there is surprising diversity in the clinical outcomes of SERT inhibitors. Such behavior may arise from the binding modes of those inhibitors with SERT. We report here on the thermodynamics of ligand‐SERT interactions determined from equilibrium and kinetic binding analyses. All drugs excepting fluvoxamine displayed remarkably similar binding thermodynamics with relatively equal contributions of entropy and enthalpy to free energy of binding. Binding enthalpies correlate with ligand polar surface areas suggesting an allowance for charged/polar interactions without enormous energetic penalties for dehydration. In the case of fluvoxamine, which possesses the greatest conformational flexibility yet binds entropically, flexible interaction is implied such that the entropic penalty expected from conformational restriction is limited. Rapid association was observed for all ligands, reflecting low energy barriers and diffusion‐limited binding reactions. The inhibitors bind in a mutually‐exclusive manner with each other as well as with 5‐HT. Taken together, the antidepressant binding site is probably solvent exposed, possibly along the substrate transport pore as predicted from structural modeling based on the leucine transporter.
Redlining is a term for race-based discriminatory acts in real estate. While this practice has been outlawed in modern America, the effects remain evident today’s society. The importance of this research is to determine if redlining is still prevalent in America and causing some racial groups to be more likely to be denied home loans over others. This paper analyzes the lasting impacts of housing discrimination in the United States by using data science applications and uses machine learning models to predict whether a loan request will be accepted or denied. We are analyzing loan approval and denial over the past decade by utilizing census data provided by the Home Mortgage Disclosure Act from the United States government. We are determining whether Black Americans and other ethnic minorities are disproportionately denied loans even with similar loan applications as other races. In other words, are they still being redlined and discriminated against based on their race. Our research revolves around the entire nation, from California to Alabama to Illinois to Michigan to determine if redlining is continuously occurring in such places and to predict loan acceptance. We determined that race was not a major factor in home loan decisions, and applicant income, along with loan amount, took precedence
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