K+ channel modulators

K+ Channel modulators

Syed Baseeruddin Alvi

Sub:- Drug Design & Molecular Modeling

INDEX

Introduction

K+ channel architecture

Selectivity filter

Ion permeation

K+ channelopathies

Drugs

INTRODUCTION

Ion channels are integral proteins

Plays a vital role in functioning of a cell

Genetic identification of ion channels

has improved our understanding……….

Ion channels enzymes…

Intracellular volume is ~10–12

Intracellular k+ concentration 100 mM

Ion permeate at the rate of

107/s

After one sec there will be no k+ in cell

Hence to b effective in altering the

membrane potential …………….

The opening & closing of channel

should be brief and fast……….

Structural basis of permeation & selectivity

K+ Channel Architecture

-KcsA

4 sub units are clustered to form to

form ion permeation pathway..

About 78 human genes have been

identified yet…..

K+ channels are tetramers

composed of four alpha subunits..

22TM/P 6TM/P

8TM/2P 4TM/2P

CLASSIFICATION OF K+ CHANNELS

2TM/P is essentially a universal feature of k+

channel

it has amino tetramerization domain, carboxy

terminal, protein interacting domain.. standard nomenclature of these channels

was proposed by Nomenclature and Drug

Classification International Union of Basic and

Clinical Pharmacology Committee on Receptor

Nomenclature and Drug classification (NC-

IUPHAR)

2 TM Family

4 TM Family

6 TM Family

How are k+ channels selective…..?

Selectivity filter

TVGYG

~12 Å

~2.5 Å

Series of stereo chemical check points

Ion permeation

k+ channel should operate under two

constraints…..

strictly selective & quick Strategies

Knock-on ion conduction

Dehydration barrier

Two conduction states

Knock-on ion conduction

The dehydration barrier

Two conduction modes

Higher conduction state 500

ps

k+ more than 20mM Lower conduction state

less than 20mM

K+ Channelopathies

Cardiac diseases (KvLQT1)

CNS diseases (KCNA1)

Deafness (KCNQ4)

Renal diseases(KCNJ1)

Metabolic diseases (SUR1)

DRUGS

K+ Channel openers

K+ channel blockers