{"title":"利用硅学方法了解潜在抗疟药物 \"MAL2-11B \"与其靶标之间的相互作用","authors":"Komalpreet Kaur Sandhu, Satinder Kaur, Rachna Hora, Prakash Chandra Mishra","doi":"10.2174/011871529X309936240821072630","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The 70 kDa heat shock proteins (Hsp70) are ubiquitous molecules that play central roles in protein homeostasis. Their nucleotide-binding domains (NBD) are associated with the J domains of 40 kDa co-chaperone 'HSP40' in performing their functions. Interruption of this interaction significantly impacts the critical ATPase activity of Hsp70s, making them dysfunctional.</p><p><strong>Methods: </strong>MAL2-11B is a dihydropyrimidine derivative that blocks Hsp70-Hsp40 interaction and hence holds the potential to be used as a drug. This Hsp70 inhibitor is a structural analogue of MAL3-101 that has proven anti-cancer and antiparasitic activity. MAL2-11B is predicted to have better drug-likeness, solubility, and absorption properties than MAL3-101. In the present study, we have therefore explored the potential of MAL2-11B as an antimalarial by using <i>in silico</i> tools.</p><p><strong>Results: </strong>Molecular docking of MAL2-11B with all <i>Plasmodium falciparum</i> Hsp70 (PfHsp70) proteins revealed its preferential affinity for two out of four homologs at the nucleotide-binding site. Detailed analysis of the docked complexes helped us to predict the kind of protein-inhibitor interactions and specific amino acid residues involved in binding.</p><p><strong>Conclusion: </strong>After <i>in vitro</i> validation, these data may be used as the groundwork for the design and development of new inhibitors and drugs against malaria.</p>","PeriodicalId":93925,"journal":{"name":"Cardiovascular & hematological disorders drug targets","volume":" ","pages":"151-162"},"PeriodicalIF":0.0000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Understanding Interactions between a Potential Antimalarial 'MAL2-11B' and its Targets using <i>In Silico</i> Methods.\",\"authors\":\"Komalpreet Kaur Sandhu, Satinder Kaur, Rachna Hora, Prakash Chandra Mishra\",\"doi\":\"10.2174/011871529X309936240821072630\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The 70 kDa heat shock proteins (Hsp70) are ubiquitous molecules that play central roles in protein homeostasis. Their nucleotide-binding domains (NBD) are associated with the J domains of 40 kDa co-chaperone 'HSP40' in performing their functions. Interruption of this interaction significantly impacts the critical ATPase activity of Hsp70s, making them dysfunctional.</p><p><strong>Methods: </strong>MAL2-11B is a dihydropyrimidine derivative that blocks Hsp70-Hsp40 interaction and hence holds the potential to be used as a drug. This Hsp70 inhibitor is a structural analogue of MAL3-101 that has proven anti-cancer and antiparasitic activity. MAL2-11B is predicted to have better drug-likeness, solubility, and absorption properties than MAL3-101. In the present study, we have therefore explored the potential of MAL2-11B as an antimalarial by using <i>in silico</i> tools.</p><p><strong>Results: </strong>Molecular docking of MAL2-11B with all <i>Plasmodium falciparum</i> Hsp70 (PfHsp70) proteins revealed its preferential affinity for two out of four homologs at the nucleotide-binding site. Detailed analysis of the docked complexes helped us to predict the kind of protein-inhibitor interactions and specific amino acid residues involved in binding.</p><p><strong>Conclusion: </strong>After <i>in vitro</i> validation, these data may be used as the groundwork for the design and development of new inhibitors and drugs against malaria.</p>\",\"PeriodicalId\":93925,\"journal\":{\"name\":\"Cardiovascular & hematological disorders drug targets\",\"volume\":\" \",\"pages\":\"151-162\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cardiovascular & hematological disorders drug targets\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/011871529X309936240821072630\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular & hematological disorders drug targets","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/011871529X309936240821072630","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Understanding Interactions between a Potential Antimalarial 'MAL2-11B' and its Targets using In Silico Methods.
Introduction: The 70 kDa heat shock proteins (Hsp70) are ubiquitous molecules that play central roles in protein homeostasis. Their nucleotide-binding domains (NBD) are associated with the J domains of 40 kDa co-chaperone 'HSP40' in performing their functions. Interruption of this interaction significantly impacts the critical ATPase activity of Hsp70s, making them dysfunctional.
Methods: MAL2-11B is a dihydropyrimidine derivative that blocks Hsp70-Hsp40 interaction and hence holds the potential to be used as a drug. This Hsp70 inhibitor is a structural analogue of MAL3-101 that has proven anti-cancer and antiparasitic activity. MAL2-11B is predicted to have better drug-likeness, solubility, and absorption properties than MAL3-101. In the present study, we have therefore explored the potential of MAL2-11B as an antimalarial by using in silico tools.
Results: Molecular docking of MAL2-11B with all Plasmodium falciparum Hsp70 (PfHsp70) proteins revealed its preferential affinity for two out of four homologs at the nucleotide-binding site. Detailed analysis of the docked complexes helped us to predict the kind of protein-inhibitor interactions and specific amino acid residues involved in binding.
Conclusion: After in vitro validation, these data may be used as the groundwork for the design and development of new inhibitors and drugs against malaria.