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<p>The neural melanocortin receptors, specifically MC3R and MC4R, play a crucial role in regulating energy homeostasis in rats. This study focuses on the theoretical evaluation of 16 orally bioavailable, small-molecule MC4R antagonists identified through experimental hit identification processes. Conceptual Density Functional Theory (CDFT) is applied to study the reactivity and stability of 16 antagonists. The physicochemical properties and metabolic activities are studied using various bioinformatics tools. Ramachandran plot analysis of MC4R protein is carried out for experimental MC4R protein structure. The active sites for MC4R protein is predicted with Active site prediction tool. MD simulations for (MC4R-antagonists) are carried out with HDOCK server. The (MC4R-16) complex showed strong binding interactions which validated the experimental results. MD simulations for Alphafold3 docked (MC4R-16) complex is carried out using Galaxy based GroMacs tools for 30&#xa0;ns due to potential shortcomings of the single-trajectory approach. Further various tools are used to evaluate the physicochemical properties, metabolic properties and toxicity assessment of the studied 16 complexes. SwissTargetPrediction webserver is used to predict the multitarget activities of the antagonists. High ionization potentials (IP), low electron affinities (EA), and larger HOMO–LUMO (HL) gaps suggest the stability and reactivity of complexes. All 16 MC4R antagonists are found to be non-toxic (MUT, TUM), with its potential safety for arrhythmia and hypertension. High gastrointestinal (GI) absorption and blood–brain barrier (BBB) permeability is observed for the antagonists. (MC4R-16) complex demonstrated system adaptability and increased conformational flexibility in loop regions, with strong hydrophobic interactions, validating the experimental findings which showed that complex 16 is effective in an aged rat model of anorexia-cachexia syndrome and has progressed to clinical trials.</p>

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Theoretical studies on safety and efficacy of 16 small-molecule MC4R antagonists as therapeutics for obesity

  • 期刊论文

  • 发表日期：

    2025年2月23日

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  • Sravani Joshi,
  • Ruby Srivastava

摘要

The neural melanocortin receptors, specifically MC3R and MC4R, play a crucial role in regulating energy homeostasis in rats. This study focuses on the theoretical evaluation of 16 orally bioavailable, small-molecule MC4R antagonists identified through experimental hit identification processes. Conceptual Density Functional Theory (CDFT) is applied to study the reactivity and stability of 16 antagonists. The physicochemical properties and metabolic activities are studied using various bioinformatics tools. Ramachandran plot analysis of MC4R protein is carried out for experimental MC4R protein structure. The active sites for MC4R protein is predicted with Active site prediction tool. MD simulations for (MC4R-antagonists) are carried out with HDOCK server. The (MC4R-16) complex showed strong binding interactions which validated the experimental results. MD simulations for Alphafold3 docked (MC4R-16) complex is carried out using Galaxy based GroMacs tools for 30 ns due to potential shortcomings of the single-trajectory approach. Further various tools are used to evaluate the physicochemical properties, metabolic properties and toxicity assessment of the studied 16 complexes. SwissTargetPrediction webserver is used to predict the multitarget activities of the antagonists. High ionization potentials (IP), low electron affinities (EA), and larger HOMO–LUMO (HL) gaps suggest the stability and reactivity of complexes. All 16 MC4R antagonists are found to be non-toxic (MUT, TUM), with its potential safety for arrhythmia and hypertension. High gastrointestinal (GI) absorption and blood–brain barrier (BBB) permeability is observed for the antagonists. (MC4R-16) complex demonstrated system adaptability and increased conformational flexibility in loop regions, with strong hydrophobic interactions, validating the experimental findings which showed that complex 16 is effective in an aged rat model of anorexia-cachexia syndrome and has progressed to clinical trials.