Kinase inhibitors as potential drugs : a molecular dynamics simulation study

مقدم أطروحة جامعية

Hammad, Iman Isam

مشرف أطروحة جامعية

Hamid, Mazin

أعضاء اللجنة

Karain, Wail
Sayyid Ahmad, Abd Allah

الجامعة

جامعة بيرزيت

الكلية

كلية العلوم

القسم الأكاديمي

دائرة الكيماء

دولة الجامعة

فلسطين (الضفة الغربية)

الدرجة العلمية

ماجستير

تاريخ الدرجة العلمية

2017

الملخص الإنجليزي

Molecular dynamics simulation and binding free energy (ΔG done to inspect the interaction between five inhibitors and PDK-1 kinase.

The free bind) values were computed using MM-GBSA and MM-PBSA free energy (ΔG energy calculation methods.

The entropic contribution of the binding free energy ΔS was computed using normal mode (NMODE) method.

The change of enthalpy (ΔH) was calculated using the equation ΔG=ΔH-T.ΔS.

There is a noticeable difference in the values of ΔG depending on the calculation method whether MM-PBSA or MM-GBSA, and this is due to the calculation different approach in each case.

PDK-1 kinase is a well validated anticancer target.

The results gave the binding modes between PDK-1 kinase and the five inhibitors, which can be used in the future in the drug design processes for cancer treatment.

The placement of water molecules in the binding sites are known.

This can be used to design better inhibitors through adding substituents to the inhibitor to replace a water molecule that binds kinase in the active site based on the creation of an inhibitor that includes a structural water mimic.

Through Molecular dynamics simulation, we identify potency PDK-1 inhibitor (5) that have unique binding to the inactive kinase conformation (DFGout).

On the other hand, inhibitors (1-4) are consider as classical ATP-competitive kinase inhibitors (Type I) which are bi nd to the active conformation DFG-in.

It was reported that type I kinase inhibitors form water-mediated hydrogen bond networks (both water molecules W1 and W2 are commonly observed) and the ligand does not extend to the water-filled cavity.

These two features distinguish type I from type II inhibitors and these two features were obvious in our study in the binding modes of inhibitors (1-4) with the PDK-1 kinase.

التخصصات الرئيسية

الكيمياء

عدد الصفحات

137

قائمة المحتويات

• APA
• MLA
• AMA

لغة النص

الإنجليزية

نوع البيانات

رسائل جامعية

رقم السجل

BIM-779852