Supawadee Sainimnuan, Aunlika Chimprasit, Supa Hannongbua, Patchreenart Saparpakorn
{"title":"利用分子动力学模拟和量子化学计算研究菲类衍生物作为选择性 PDE5 抑制剂的相互作用模式的作用。","authors":"Supawadee Sainimnuan, Aunlika Chimprasit, Supa Hannongbua, Patchreenart Saparpakorn","doi":"10.1007/s11030-024-10944-3","DOIUrl":null,"url":null,"abstract":"<p><p>Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.\",\"authors\":\"Supawadee Sainimnuan, Aunlika Chimprasit, Supa Hannongbua, Patchreenart Saparpakorn\",\"doi\":\"10.1007/s11030-024-10944-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.</p>\",\"PeriodicalId\":708,\"journal\":{\"name\":\"Molecular Diversity\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Diversity\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1007/s11030-024-10944-3\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Diversity","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1007/s11030-024-10944-3","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Role of interaction mode of phenanthrene derivatives as selective PDE5 inhibitors using molecular dynamics simulations and quantum chemical calculations.
Phosphodiesterase type 5 (PDE5) inhibitors play a crucial role in blocking PDE5 to improve erectile dysfunction (ED). However, most PDE5 drugs revealed side effects including the loss of vision due to the PDE6 inhibition. Phenanthrene derivatives isolated from E. macrobulbon were previously reported as PDE5 inhibitors. Two phenanthrene derivatives (cpds 1-2) revealed better inhibition to PDE5 than PDE6 and cpd 1 is more selective to PDE5 than cpd 2. To elucidate why the phenanthrene derivatives could inhibit PDE5 and PDE6, their binding modes were investigated using molecular dynamics simulations and quantum chemical calculations, as compared to the PDE5 drugs. From the results, all four drugs and phenanthrene derivatives revealed similar π-π interactions to Phe820 in PDE5. Additional H-bond interaction to Gln817 in PDE5 resulted in better PDE5 inhibition of vardenafil and tadalafil. Moreover, cpds 1-2 were able to form the H-bond interaction with Asp764 in PDE5. In the case of the PDE6, the loss of π-π interaction to Phe776 and H-bond interaction to Gln773 indicated the important points for losing the PDE6 inhibition. In conclusion, to develop the new potent PDE5 inhibitors, not only the important interaction with PDE5 but also the interaction with PDE6 should be considered. In phenanthrene derivatives, the middle ring was significant to form π-π interactions to Phe820 in PDE5 and hydroxyl substituent was also the key part to form the H-bond interaction with Asp764 in PDE5. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated the stability of the system. The bioavailability, drug-likeness, and pharmacokinetics of phenanthrene derivatives were also predicted. These derivatives revealed good drug-likeness and GI absorption. The obtained results showed that phenanthrene derivatives could be interesting for the development of PDE5 inhibitors in the future.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;