I suggest you read the works of Robert Copeland, especially the book "Evaluation of Enzyme Inhibitors in Drug Discovery." A particular emphasis is on the benefit of long residence time inhibitors in relation to pharmacokinetics.

Dear Farooq,

In addition to what Adam has indicated, the following is an answer to the first sub-question "What are KV activators? How do they differ from K activators? "

K activators:

Potassium channels function to conduct potassium ions down their electrochemical gradient, doing so both rapidly and selectively. Biologically, these channels act to set or reset the resting potential in many cells. In excitable cells, such as neurons, the delayed counter flow of potassium ions shapes the action potential.

A potassium channel activators (openers) is a type of drug which facilitates ion transmission through potassium channels.

Some examples include:

Diazoxide: vasodilator used for hypertension, smooth muscle relaxing activity

Minoxidil:  vasodilator used for hypertension, also used to treat hair loss

Nicorandil:  vasodilator used to treat angina

Pinacidil

Retigabine:  an anticonvulsant

Flupirtine, analgesic with muscle relaxant and anticonvulsant properties.

KV activators: Voltage-gated Potassium (KV) Channels

 Voltage-gated potassium channels (KV) belong to the 6-TM family of potassium channel that also comprises the Ca2+-activated Slo (actually 7-TM) and the Ca2+-activated SK subfamilies. The α-subunits contain a single pore-forming region and combine to form tetramers.

 Flupirtine maleate

KV7 channel activator

 ICA 069673

KV7.2/KV7.3 channel opener

 ICA 110381

KV7.2/7.3 activator; displays anticonvulsant properties

 L-364,373

KV7.1 channel activator, activates IKs

ML 213

KV7.2 and KV7.4 channel opener

 ML 277

Selective Kv7.1 (KCNQ1) potassium channel activator; augments IKs current

 NS 1643

KV11.1 (hERG) channel activator; antiarrhythmic

 NS 3623

KV11.1 (hERG) channel activator; antiarrhythmic

 NS 5806

KV4.3 channel activator

 PD 118057

Selective KV11.1 (hERG) channel activator

 QO 58 New product

Kv7 channel opener

https://en.wikipedia.org/wiki/Potassium_channel_opener

https://www.tocris.com/pharmacologicalBrowser.php?ItemId=47688#.V8oENfl97IU

Hoping this will be helpful,

Rafik

Hi Farooq,

    K activators are those small-molecules that, upon binding to an allosteric site on the target, increases the affinity of the target for its substrate. This is usually seen with enzymes that show sigmoidicity in their substrate vs velocity plots. V type activators, on the other hand, are those that increase the velocity of substrate to product conversion. Though I have not come across a case where both V-type and K-type activation is shown by an enzyme on the same substrate molecules, it is well known that some enzymes show V-type activation for one substrate molecule while K-type activation for others. A prominent example is the cN-II class of cytosolic 5' nucleotidases. You can also refer to my following paper where I have shown that cN-II from legionella pneumophila shows V-type activation for pNPP hydrolysis and K-type activation for GMP hydrolysis.

B Srinivasan et al., (2014) Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila. FEBS Journal 281 (6), 1613-1628 

I hope my answer helps.

you may also check our following papers:

Article First Universal Pharmacophore Model for hERG1 K+ Channel Activators

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