Dataset Information

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores.

ABSTRACT: A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.

SUBMITTER: Truax NJ

PROVIDER: S-EPMC7023684 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of <i>Sinularia</i> Natural Product Tricyclic Cores.

Truax Nathanyal J NJ Ayinde Safiat S Van Khoi K Liu Jun O JO Romo Daniel D

Organic letters 20190909 18

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from <i>Sinularia</i> soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates ...[more]

PMID: 31498642

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Project description:Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the development of new drugs aiming at satiety and appetite control targets. Among the reported satiety signaling targets, 5HT2C receptor plays a crucial role in decreasing appetite and has become a promising target for the development of anti-obesity drugs. Lorcaserin, a 5HT2C receptor agonist and the only drug available in the market, was designed based on the receptor mechanism of action. Due to limited drug options available and considering the adverse drug effects of Lorcaserin, the development of new drugs which are highly specific toward the 5HT2C target and with lesser side effects is essential. The present study is majorly focused on developing new 5HT2C agonists through computational approaches like screening, docking, and simulation using Phase, QikProp, Glide and Desmond applications of the Schrodinger suite. Screening protocols resulted in eight best hit molecules with affinity for the receptor and among them, five hits displayed binding affinity toward the conserved residue Asp 134 of the receptor. The stability of the five molecules in complex with the 5HT2C receptor was studied through molecular dynamic simulations. Three molecules, ZINC32123870, ZINC40312983 and ZINC32124535, maintained stable interactions with the Asp 134 residue throughout the 50 ns simulation run time. Further, due to the high sequence similarity seen among the receptors of 5HT2 family, the three potential hits were cross validated against other subtypes 5HT2A and 5HT2B of the 5HT2 family to determine the specificity of the molecules against the target. Among the three hits, ZINC32124535 was identified as the best potential hit based on the hydrogen bond interaction percentage with Asp residue [5HT2A (Asp 155:60%); 5HT2B (Asp155: No interaction); 5HT2C (Asp 134:86%)]. The ZINC32124535 molecule produced one salt bridge and hydrogen bond interactions with Asp 134, alike the known drug Lorcaserin. Based on the results, ZINC32124535 was identified as the best potential hit against the 5HT2C receptor.

Dataset Information

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores.

Publications

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of <i>Sinularia</i> Natural Product Tricyclic Cores.

Similar Datasets

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