Kinase inhibitors as potential drugs : a molecular dynamics simulation study

Dissertant

Hammad, Iman Isam

Thesis advisor

Hamid, Mazin

Comitee Members

Karain, Wail
Sayyid Ahmad, Abd Allah

University

Birzeit University

Faculty

Faculty of Science

Department

Department of Chemistry

University Country

Palestine (West Bank)

Degree

Master

Degree Date

2017

English Abstract

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.

Main Subjects

Chemistry

No. of Pages

137

Table of Contents

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Language

English

Data Type

Arab Theses

Record ID

BIM-779852