Monoamin oksidaz tip B enzimine yönelik ilaç moleküllerinin moleküler dinamik simulasyon analizleri
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Date
2004
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Kadir Has Üniversitesi
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Abstract
İlaç moleküllerini bağlı bulundukları enzim içerisinde simüle edip elde edilen veriler yardımıyla inhibitor ile enzimin bağlanma dinamiğinin analizi ve serbest enerjilerinin hesaplanması, çalışmamızın temelini oluşturmaktadır. Simülasyon boyunca elde edilen veriler moleküler mekanik parametreler kullanılarak hesaplanmıştır. Simülasyon için her bir model ilaç bileşiği hem su içerisinde, hemde protein (enzim) içerisinde olacak şekilde, iki ayrı ortamda, koordinat dosyaları oluşturuldu. Simülasyon boyunca ilaç ve enzim moleküllerinin atomları arasındaki, etkileşim enerjileri olarak da adlandırılan Van Der Waals (VDW) ve elektrostatik enerjiler kaydedildi. Elde edilen enerji verilerinden lineer etkileşim modeli (LIE) kullanılarak, her bir ilacın inhibisyon katsayısı elde edildi. İlaç molekülünün, protein içindeki enerji ile sudaki enerji farkı, ilacın bağlanma serbest enerjisini vermektedir. Bu çalışmada monoamin oksidaz enziminin, parjilin ve selejilin ilaçlan ile olan etkileşiminin enerjetik hesaplamaları yapılmıştır. Elde edilen veriler selejilin molekülünün parjiline göre daha kuvvetli bağlandığını göstermektedir. Selejilin ve parjilinin bağlanma serbest enerjileri deneysel yöntemler ile yapılan çalışmalarla uyuşmaktadır. Simülasyon sırasında moleküler sisteme dışarıdan su molekülleri eklenmiştir. İlaç moleküllerinin atomlarının parsiyel yük hesaplamaları, yarı ampirik (semi-empirical) yöntem, AMMP programının MOM yöntemi (method of moments) kullanılarak yapılmıştır (1 ).
In this study we aimed to simulate an enzyme-inhibitor complex to gain insight into the dynamics of binding an inhibitor (drug substance) to an enzyme and to calculate the binding free energy of a given inhibitor. Throughout the simulation, we collected data by using molecular mechanics parameters. To carry out the simulation, we prepared coordinate files of each of the model drug compounds separately, in both aqueous and protein (enzyme) mediums. During the simulation, we recorded interaction energies, such as Van der Waals and electrostatic, between drugs and enzyme atoms. Then, using the Linear Interaction Energy (LIE) model, we calculated, from the data of energy obtained, the inhibition constants of each drug molecule. We found that the free energy through the binding of given drug molecules can be calculated from the energy difference of the drug in aqueous and protein environments. In this study, we calculated the interacting energy of pargyline and selegyline drug molecules for a monoamine oxidase (MAO) enzyme. The resulting data showed us that selegyline molecules bind more tightly to an MAO enzyme than pargyline molecules do. The predicted values of binding constants of selegyline and pargyline are consistent with the experimental values. During simulation, we explicitly added water molecules to the system. We calculated the partial charges of drug compounds by using the MOM (Method of Moments) of AMMP (Another Molecular Mechanics Program), which is a semi-empirical method (1).
In this study we aimed to simulate an enzyme-inhibitor complex to gain insight into the dynamics of binding an inhibitor (drug substance) to an enzyme and to calculate the binding free energy of a given inhibitor. Throughout the simulation, we collected data by using molecular mechanics parameters. To carry out the simulation, we prepared coordinate files of each of the model drug compounds separately, in both aqueous and protein (enzyme) mediums. During the simulation, we recorded interaction energies, such as Van der Waals and electrostatic, between drugs and enzyme atoms. Then, using the Linear Interaction Energy (LIE) model, we calculated, from the data of energy obtained, the inhibition constants of each drug molecule. We found that the free energy through the binding of given drug molecules can be calculated from the energy difference of the drug in aqueous and protein environments. In this study, we calculated the interacting energy of pargyline and selegyline drug molecules for a monoamine oxidase (MAO) enzyme. The resulting data showed us that selegyline molecules bind more tightly to an MAO enzyme than pargyline molecules do. The predicted values of binding constants of selegyline and pargyline are consistent with the experimental values. During simulation, we explicitly added water molecules to the system. We calculated the partial charges of drug compounds by using the MOM (Method of Moments) of AMMP (Another Molecular Mechanics Program), which is a semi-empirical method (1).