Molekularna dinamika u studijama modulatora aktivnosti γ-sekretaze za liječenje Alzheimerove bolesti

Background: Alzheimer's disease is the most expensive disease for healthcare providers in developed countries in the 21st century, and the most lucrative market for the pharmaceutical industry. Changes in the activity of the membrane embedded protease γ-secretase can result in a decreased clearance of amyloid proteins and the development of Alzheimer's disease. We analyzed the catalytic mechanism of γ-secretase using some of the best known drug candidates; semagacestat, DAPT, avagacestat, and LY411-575. Molecular docking studies were first used for the identification of binding sites, and multi-scale molecular dynamic simulations were used for the description of binding interactions. Results: Molecular dynamics studies show that the proteolytic channel of γ-secretase, as well as surface enzyme binding sites, can bind several drug candidates at the same time. There are three surface binding sites that bind ligands over a time period of 300 nanoseconds. At least two ligands can bind inside the open active site tunnel when there is no substrate present. Each step in substrate catalysis has a different affinity for different drug candidates. Transient interactions between positive and negative amino acids in the active site can regulate the catalytic cleavages of amyloid beta precursor protein. Conclusion: Multiple biphasic modulators can bind to γ-secretase simultaneously and modulate its Aβ production. The biphasic modulators that activate γ-secretase and act as competitive inhibitors could be the most promising drug for Alzheimer's disease. Molecular dynamics can be used to design and develop such drug candidates.Pozadina: Alzheimerova bolest najskuplja je bolest za pružatelje zdravstvenih usluga u razvijenim zemljama u 21. stoljeću.Također je najunosnije tržište za farmaceutsku industriju. Promjene u aktivnosti proteina γ-sekretaze mogu rezultirati smanjenim pročišćavanjem amiloidnih proteina i razvojem Alzheimerove bolesti. Analizirali smo katalitički mehanizam γ-sekretaze koristeći neke od najpoznatijih kandidata za lijekove; semagacestat, DAPT, avagacestat i LY411-575. Studije molekularnog vezanja najprije su korištene za prepoznavanje mjesta vezanja, a za opis interakcija vezanja korištene su simulacije molekularne dinamike. Rezultati: Studije molekularne dinamike pokazuju da proteolitički kanal γ-sekretaze, kao i mjesta vezanja na enzimskoj površini, mogu istovremeno vezati nekoliko kandidata za lijek. Postoje tri površinska mjesta vezivanja koja vežu ligande u vremenskom periodu od 300 nanosekundi. Barem dva liganda mogu se vezati unutar otvorenog tunela aktivnog mjesta kada nema supstrata. Svaki korak katalize supstrata ima različit afinitet za različite kandidate za lijek. Privremene interakcije između pozitivnih i negativnih aminokiselina na aktivnom mjestu mogu regulirati katalitičko cijepanje proteina prekursora amiloida beta. Zaključak: Višestruki dvofazni modulatori mogu se istovremeno vezati za γ-sekretazu i modulirati njenu proizvodnju Aβ. Dvofazni modulatori koji aktiviraju γ-sekretazu i djeluju kao kompetitivni inhibitori mogli bi biti najperspektivniji lijek za Alzheimerovu bolest. Molekularna dinamika može se koristiti za oblikovanje i razvoj takvih kandidata za lijekove

Molekularna dinamika u studijama modulatora aktivnosti γ-sekretaze za liječenje Alzheimerove bolesti

Background: Alzheimer's disease is the most expensive disease for healthcare providers in developed countries in the 21st century, and the most lucrative market for the pharmaceutical industry. Changes in the activity of the membrane embedded protease γ-secretase can result in a decreased clearance of amyloid proteins and the development of Alzheimer's disease. We analyzed the catalytic mechanism of γ-secretase using some of the best known drug candidates; semagacestat, DAPT, avagacestat, and LY411-575. Molecular docking studies were first used for the identification of binding sites, and multi-scale molecular dynamic simulations were used for the description of binding interactions. Results: Molecular dynamics studies show that the proteolytic channel of γ-secretase, as well as surface enzyme binding sites, can bind several drug candidates at the same time. There are three surface binding sites that bind ligands over a time period of 300 nanoseconds. At least two ligands can bind inside the open active site tunnel when there is no substrate present. Each step in substrate catalysis has a different affinity for different drug candidates. Transient interactions between positive and negative amino acids in the active site can regulate the catalytic cleavages of amyloid beta precursor protein. Conclusion: Multiple biphasic modulators can bind to γ-secretase simultaneously and modulate its Aβ production. The biphasic modulators that activate γ-secretase and act as competitive inhibitors could be the most promising drug for Alzheimer's disease. Molecular dynamics can be used to design and develop such drug candidates.Pozadina: Alzheimerova bolest najskuplja je bolest za pružatelje zdravstvenih usluga u razvijenim zemljama u 21. stoljeću.Također je najunosnije tržište za farmaceutsku industriju. Promjene u aktivnosti proteina γ-sekretaze mogu rezultirati smanjenim pročišćavanjem amiloidnih proteina i razvojem Alzheimerove bolesti. Analizirali smo katalitički mehanizam γ-sekretaze koristeći neke od najpoznatijih kandidata za lijekove; semagacestat, DAPT, avagacestat i LY411-575. Studije molekularnog vezanja najprije su korištene za prepoznavanje mjesta vezanja, a za opis interakcija vezanja korištene su simulacije molekularne dinamike. Rezultati: Studije molekularne dinamike pokazuju da proteolitički kanal γ-sekretaze, kao i mjesta vezanja na enzimskoj površini, mogu istovremeno vezati nekoliko kandidata za lijek. Postoje tri površinska mjesta vezivanja koja vežu ligande u vremenskom periodu od 300 nanosekundi. Barem dva liganda mogu se vezati unutar otvorenog tunela aktivnog mjesta kada nema supstrata. Svaki korak katalize supstrata ima različit afinitet za različite kandidate za lijek. Privremene interakcije između pozitivnih i negativnih aminokiselina na aktivnom mjestu mogu regulirati katalitičko cijepanje proteina prekursora amiloida beta. Zaključak: Višestruki dvofazni modulatori mogu se istovremeno vezati za γ-sekretazu i modulirati njenu proizvodnju Aβ. Dvofazni modulatori koji aktiviraju γ-sekretazu i djeluju kao kompetitivni inhibitori mogli bi biti najperspektivniji lijek za Alzheimerovu bolest. Molekularna dinamika može se koristiti za oblikovanje i razvoj takvih kandidata za lijekove

Molekularna dinamika u studijama modulatora aktivnosti γ-sekretaze za liječenje Alzheimerove bolesti

Background: Alzheimer's disease is the most expensive disease for healthcare providers in developed countries in the 21st century, and the most lucrative market for the pharmaceutical industry. Changes in the activity of the membrane embedded protease γ-secretase can result in a decreased clearance of amyloid proteins and the development of Alzheimer's disease. We analyzed the catalytic mechanism of γ-secretase using some of the best known drug candidates; semagacestat, DAPT, avagacestat, and LY411-575. Molecular docking studies were first used for the identification of binding sites, and multi-scale molecular dynamic simulations were used for the description of binding interactions. Results: Molecular dynamics studies show that the proteolytic channel of γ-secretase, as well as surface enzyme binding sites, can bind several drug candidates at the same time. There are three surface binding sites that bind ligands over a time period of 300 nanoseconds. At least two ligands can bind inside the open active site tunnel when there is no substrate present. Each step in substrate catalysis has a different affinity for different drug candidates. Transient interactions between positive and negative amino acids in the active site can regulate the catalytic cleavages of amyloid beta precursor protein. Conclusion: Multiple biphasic modulators can bind to γ-secretase simultaneously and modulate its Aβ production. The biphasic modulators that activate γ-secretase and act as competitive inhibitors could be the most promising drug for Alzheimer's disease. Molecular dynamics can be used to design and develop such drug candidates.Pozadina: Alzheimerova bolest najskuplja je bolest za pružatelje zdravstvenih usluga u razvijenim zemljama u 21. stoljeću.Također je najunosnije tržište za farmaceutsku industriju. Promjene u aktivnosti proteina γ-sekretaze mogu rezultirati smanjenim pročišćavanjem amiloidnih proteina i razvojem Alzheimerove bolesti. Analizirali smo katalitički mehanizam γ-sekretaze koristeći neke od najpoznatijih kandidata za lijekove; semagacestat, DAPT, avagacestat i LY411-575. Studije molekularnog vezanja najprije su korištene za prepoznavanje mjesta vezanja, a za opis interakcija vezanja korištene su simulacije molekularne dinamike. Rezultati: Studije molekularne dinamike pokazuju da proteolitički kanal γ-sekretaze, kao i mjesta vezanja na enzimskoj površini, mogu istovremeno vezati nekoliko kandidata za lijek. Postoje tri površinska mjesta vezivanja koja vežu ligande u vremenskom periodu od 300 nanosekundi. Barem dva liganda mogu se vezati unutar otvorenog tunela aktivnog mjesta kada nema supstrata. Svaki korak katalize supstrata ima različit afinitet za različite kandidate za lijek. Privremene interakcije između pozitivnih i negativnih aminokiselina na aktivnom mjestu mogu regulirati katalitičko cijepanje proteina prekursora amiloida beta. Zaključak: Višestruki dvofazni modulatori mogu se istovremeno vezati za γ-sekretazu i modulirati njenu proizvodnju Aβ. Dvofazni modulatori koji aktiviraju γ-sekretazu i djeluju kao kompetitivni inhibitori mogli bi biti najperspektivniji lijek za Alzheimerovu bolest. Molekularna dinamika može se koristiti za oblikovanje i razvoj takvih kandidata za lijekove

Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer’s Disease

Significance: The majority of the drugs which target membrane-embedded protease γ-secretase show an unusual biphasic activation–inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic drugs that can facilitate cognitive decline in patients with Alzheimer’s disease. Initial mechanistic studies showed that the biphasic drugs, and pathogenic mutations, can produce the same type of changes in γ-secretase activity. Results: DAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and a biphasic activation–inhibition dose-response for amyloid-β-40 products in SH-SY5 cells. Multiscale molecular dynamics studies have shown that all four drugs bind to the most mobile parts in the presenilin structure, at different ends of the 29 Å long active site tunnel. The biphasic dose-response assays are a result of the modulation of γ-secretase activity by the concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate γ-secretase by facilitating the opening of the active site tunnel, when the rate-limiting step is the tunnel opening, and the formation of the enzyme–substrate complex. The drugs inhibit γ-secretase as uncompetitive inhibitors by binding next to the substrate, to dynamic enzyme structures which regulate processive catalysis. The drugs can modulate the production of different amyloid-β catalytic intermediates by penetration into the active site tunnel, to different depths, with different flexibility and different binding affinity. Conclusions: Biphasic drugs and pathogenic mutations can affect the same dynamic protein structures that control processive catalysis. Successful drug-design strategies must incorporate transient changes in the γ-secretase structure in the development of specific modulators of its catalytic activity