Scholarlink

<p>Malaria remains a significant global health problem; with the potential for developing resistance to conventional antimalarials justifying novel therapeutic approaches. This study investigates the potential of microalgal metabolites as dual-inhibitors of <i>Plasmodium falciparum</i> glutathione S-transferase (<i>Pf</i>GST) and apical membrane antigen 1 (AMA1); two of the most important proteins in parasite survival and host cell invasion. By high-throughput molecular docking simulations; we studied binding energy distributions; conformational characteristics by principal component analysis; pharmacophoric and pharmacokinetic research with structure-activity relationships of its inhibitors. Our findings indicate various patterns of interactions: <i>Pf</i>GST exhibits a unimodal distribution of binding energy with a maximum at -7.2&#xa0;kcal/mol; whereas AMA1 exhibits a bimodal distribution with minimum at -6.8 and − 8.3&#xa0;kcal/mol; suggesting various mechanisms of binding. Specifically; platencin was among the most potent dual-inhibitors with binding energies of -7.30&#xa0;kcal/mol to <i>Pf</i>GST and − 8.20&#xa0;kcal/mol to AMA1. Pharmacophoric characteristics were found to be the hydrogen-bond acceptors; hydrophobic centers; and aromatic rings as determinants of dual-target activity; the optimal dual-target inhibitory potential occurring with compounds of balanced physicochemical properties. High-resolution molecular interaction mapping validated that while the two targets identify overlapping classes of interactions with the metabolites; <i>Pf</i>GST interaction is dominated by hydrophobic contacts and AMA1 exploits higher electrostatic complementarity and hydrogen-bonding networks. ADMET profiling also revealed favorable drug-likeness in dual-inhibitory compounds of intermediate molecular size (420–500 Da) and moderate lipophilicity (LogP 3–6). This study provides a structural basis for rationale design of antimalarial compounds from microalgal metabolites. Our findings confirm the conformational selection hypothesis; in which these compounds selectively bind to and stabilize protein conformations that inhibit parasite function; possibly circumventing known resistance mechanisms.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Computational discovery of microalgal metabolites as dual-target inhibitors against Plasmodium falciparum glutathione S-transferase and apical membrane antigen 1 for resistance-circumventing antimalarial therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月13日

查看全文
  • Oluwaseun E. Agboola,
  • Samuel S. Agboola,
  • Abel K. Oyebamiji,
  • Zainab A. Ayinla,
  • Oluranti E. Olaiya,
  • Oluwatoyin M. Oyinloye,
  • Folake Olayinka Olojo,
  • Foluso O. Osunsanmi,
  • Seun F. Akomolafe,
  • Basiru O. Ajiboye,
  • Babatunji E. Oyinloye

摘要

Malaria remains a significant global health problem; with the potential for developing resistance to conventional antimalarials justifying novel therapeutic approaches. This study investigates the potential of microalgal metabolites as dual-inhibitors of Plasmodium falciparum glutathione S-transferase (PfGST) and apical membrane antigen 1 (AMA1); two of the most important proteins in parasite survival and host cell invasion. By high-throughput molecular docking simulations; we studied binding energy distributions; conformational characteristics by principal component analysis; pharmacophoric and pharmacokinetic research with structure-activity relationships of its inhibitors. Our findings indicate various patterns of interactions: PfGST exhibits a unimodal distribution of binding energy with a maximum at -7.2 kcal/mol; whereas AMA1 exhibits a bimodal distribution with minimum at -6.8 and − 8.3 kcal/mol; suggesting various mechanisms of binding. Specifically; platencin was among the most potent dual-inhibitors with binding energies of -7.30 kcal/mol to PfGST and − 8.20 kcal/mol to AMA1. Pharmacophoric characteristics were found to be the hydrogen-bond acceptors; hydrophobic centers; and aromatic rings as determinants of dual-target activity; the optimal dual-target inhibitory potential occurring with compounds of balanced physicochemical properties. High-resolution molecular interaction mapping validated that while the two targets identify overlapping classes of interactions with the metabolites; PfGST interaction is dominated by hydrophobic contacts and AMA1 exploits higher electrostatic complementarity and hydrogen-bonding networks. ADMET profiling also revealed favorable drug-likeness in dual-inhibitory compounds of intermediate molecular size (420–500 Da) and moderate lipophilicity (LogP 3–6). This study provides a structural basis for rationale design of antimalarial compounds from microalgal metabolites. Our findings confirm the conformational selection hypothesis; in which these compounds selectively bind to and stabilize protein conformations that inhibit parasite function; possibly circumventing known resistance mechanisms.