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      Novel Thiazolidinedione and Rhodanine Derivatives Regulate Glucose Metabolism, Improve Insulin Sensitivity, and Activate the Peroxisome Proliferator-Activated γ Receptor

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          Abstract

          Sixteen novel thiazolidinedione (TZD) and rhodanine (RD) derivatives were designed and synthesized by introducing a pyrimidine moiety at different sites of pioglitazone’s structure. The effects of synthesized compounds on regulating glucose metabolism, improving insulin sensitivity, and activating the peroxisome proliferator-activated γ receptor (PPAR-γ) were evaluated in βTC6 cells. Compounds TZDs # 7a, 7b, 7c, and 29 reduced the basal insulin secretion by ∼20.0–67.0% and increased insulin secretion stimulated by glucose by ∼25.0–50.0% compared to control. Compounds TZDs # 14 and 21 and RDs # 33a–b and 33df increased basal insulin secretion by ∼20.0–100.0%, while its glucose-stimulated secretion remained unchanged. These findings suggested that the former compounds can act as antihypoglycemic during fasting and antihyperglycemic during postprandial conditions. The latter compounds should be administered before meals to avoid their hypoglycemic effect. Additionally, both TZDs and RDs improved insulin sensitivity by increasing glucose uptake by 17.0–155.0% relative to control. In silico molecular docking of synthesized drugs onto the PPAR-γ structure revealed exothermic binding modes through hydrogen bonding, van der Waals forces, and π–π stacking with binding affinities of −6.02 to −9.70 kcal/mol. Insights into the structure–activity relationship revealed that the introduction of pyrimidine linked to sulfonyl or peptide groups accounted for increased antidiabetic activity. These results demonstrated novel TZDs and RDs with high potency in stimulating insulin secretion, enhancing insulin sensitivity, and activating PPAR-γ relative to pioglitazone. They are recommended for further development as potential antidiabetic agents.

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          Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments.

          Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.
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            Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.

            A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
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              Automatic atom type and bond type perception in molecular mechanical calculations.

              In molecular mechanics (MM) studies, atom types and/or bond types of molecules are needed to determine prior to energy calculations. We present here an automatic algorithm of perceiving atom types that are defined in a description table, and an automatic algorithm of assigning bond types just based on atomic connectivity. The algorithms have been implemented in a new module of the AMBER packages. This auxiliary module, antechamber (roughly meaning "before AMBER"), can be applied to generate necessary inputs of leap-the AMBER program to generate topologies for minimization, molecular dynamics, etc., for most organic molecules. The algorithms behind the manipulations may be useful for other molecular mechanical packages as well as applications that need to designate atom types and bond types.
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                Author and article information

                Journal
                ACS Omega
                ACS Omega
                ao
                acsodf
                ACS Omega
                American Chemical Society
                2470-1343
                25 January 2024
                06 February 2024
                : 9
                : 5
                : 5463-5484
                Affiliations
                []Department of Chemistry, College of Science, United Arab Emirates University , Al-Ain 15551, United Arab Emirates
                []Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University , Al-Ain 17666, United Arab Emirates
                [§ ]College of Pharmacy, Al Ain University , Abu Dhabi 112612, United Arab Emirates
                Author notes
                Author information
                https://orcid.org/0000-0002-2240-8037
                https://orcid.org/0000-0002-3201-9852
                Article
                10.1021/acsomega.3c07149
                10851269
                6bdda6b8-c7bd-4410-b2e0-4bace90b4c14
                © 2024 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 September 2023
                : 03 January 2024
                : 29 December 2023
                Funding
                Funded by: United Arab Emirates University, doi 10.13039/501100006013;
                Award ID: 31S030
                Funded by: United Arab Emirates University, doi 10.13039/501100006013;
                Award ID: G00001322
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                Article
                Custom metadata
                ao3c07149
                ao3c07149

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