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Advanced Bioinformatics Lecture 6: Pharmacology and drug development. ZHU FENG [email protected] Innovative Drug Research Centre in CQU. 创新药物研究与生物信息学实验室. Table of Content. Modern drug development Drug & corresponding target Mechanism of drug binding

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Advanced Bioinformatics

Lecture 6: Pharmacology and drug development


[email protected]

Innovative Drug Research Centre in CQU


Table of content
Table of Content

Modern drug development

Drug & corresponding target

Mechanism of drug binding

Mechanism of drug action

Adrenoceptor cardiac function


2013 ranking of the global top 10 pharmaceutical companies based on revenue











Revenue in billion U.S. dollars

Traditional drug design based on revenue

  • Random screening against disease assays

  • Natural products, synthetic chemicals, etc

  • Long design cycle: 7-12 years

  • High cost: 350 million USD per marketed drug

  • Too slow and costly to meet demand

  • Drug Discovery Today 2, 72-78 (1997)


Modern drug development based on revenue

  • Rational drug design and testing

  • Speed-up screening process

  • Efficient screening (focused, target directed)

  • Computer aided drug design (target directed)

  • Integration of testing into design process

  • Fail drugs fast (remove hopeless ones AEAP)


Strategies for improving design cycle based on revenue

  • Smart screening:

  • High-throughput robotic screening

  • Diversity of chemical compounds:

  • Combinatorial chemistry

  • High expectation

  • Nature 384 Suppl., 2-7 (1996)


Any other alternative approach? based on revenue

  • Current situation:

  • Molecular mechanism of disease processes, structural biology.

  • Rising cost of experimental equipment and resources.

  • Computer revolution (low cost, high power).

  • Software development.

  • Natural conclusion: computer approach?


Strategies for improving design cycle based on revenue

  • Computer-aided drug design:

  • Receptor 3D structure unknown

  • Receptor-based drug design (QSAR)

  • Receptor 3D structure known

  • Ligand-based drug design (Docking)

  • Science 257, 1078-1082 (1992)


The stages of development of a ‘typical’ new drug based on revenue

Overall cost per marketed compound is ₤250-500 million and the typical time scale is 8-12 years. Only about 1 in 12 entering development succeeds in reaching the market


Key go/no-go decisions for developing a drug based on revenue

Key decision gates in drug development

Drug candidate selection based on revenue

Key questions and pivotal studies









Drug safety indicators based on revenue

Key questions and pivotal studies



Safety margin



Effects on heart

Effects on lung


Drug & corresponding target based on revenue


Drug target: receptor based on revenue

  • Receptors are the sites at which molecules such as hormones and neurotransmitters are recognised.

  • A drug that binds to a receptor can be:

    • Agonist: trigger the same events as the native ligand.

    • Antagonist: stop bind of the native agent without eliciting a response

  • There are four ‘superfamilies’ of receptors


Types of receptor- based on revenueeffector linkage


Drug target: enzyme based on revenue

Proteins catalyzing reactions required for cellular function.

Specific for particular substrate or family of substrates.

Inhibitor restricts action of enzyme on its substrate.

Inhibitors may be irreversible or reversible.

Reversible inhibitors: Competitive & Non-competitive.

Enzyme inhibitors might be seen to allow very ‘fine control’ of cellular processes.


Drug target: nucleic acids based on revenue

  • Designing compounds that can distinguish target nucleic acid sequences is not yet achievable.

  • There are compounds with planar aromatic regions that bind in-between the base pairs of DNA or to the DNA grooves.

  • These generally inhibit the processes of DNA manipulation required for protein synthesis and cell division.

  • Suitable for aiming at promoting cell death.


Mechanisms and specificity of drug binding trial targets

  • The majority of binding and recognition occurs through non-covalent interactions.

  • These govern:

  • The folding of proteins and DNA.

  • The association of membranes.

  • Molecular recognition (e.g. interaction between an enzyme and its substrate or the binding of an antibody).

  • They are generally weak and operate only over short distances.

  • As a result large numbers of these interactions are necessary for stability, requiring a high degree of complementarity between binding groups and molecules.


Drug binding site in a cavity of protein trial targets

HIV-1 protease


Mechanism of drug binding and actions trial targets

Lock and key: blocking => stopping of protein function

HIV-1 protease complex with SB203238


Covalent bonds trial targets

  • The ‘sharing’ of a pair of electrons between two atoms.

  • A very stable interaction

  • Requires hundreds of kilojoules (kJ) to disrupt

  • Compounds that inhibit enzymes through formation of covalent interactions are called ‘suicide inhibitors’.

  • Not all covalent bond formation is irreversible

  • Hydrolysis

  • Action of repairing proteins


Non-covalent interactions trial targets

  • The forces involved are:

  • Hydrogen bonds

  • van der Waals forces

  • Ionic / electrostatic interactions

  • Hydrophobic interactions

  • Generally, such interactions are weak:

  • Vary from 4-30 kJ/mol


Selectivity, toxicity and therapeutic index trial targets

  • Drugs may bind to both their desired target and to other molecules in an organism.

  • If interactions with other targets are negligible then a drug is said to be specific.

  • In most cases drugs will show a non-exclusive preference for their target - selective.

  • The interaction with both their intended target and other molecules can lead to undesirable effects (side effects).


Selectivity, toxicity and therapeutic index trial targets

  • Establish the concentrations at which the drug exerts its beneficial effect and where the level of side effects becomes unacceptable.

  • Commonly used values are ED50 and LD50.

  • For obvious reasons LD50 tests are not carried out on human volunteers!

  • One measure of the margin of safety is the therapeutic index. Therapeutic index = LD50 / ED50

  • Drugs with low therapeutic indices are only used in ‘life or death’ type situations.


Agonists & antagonists trial targets

  • Activity of a drug is the result of two independent factors:

  • Affinity is the ability of a drug to bind to its receptor

  • Efficacy is the ability of the bound drug to elicit a response

  • There are 2 classes of agonist

  • Full agonists – which elicit the maximum possible response at some concentration

  • Partial agonists – which never elicit the maximum possible response from the receptor

  • There are 2 classes of antagonist

  • Competitive – which compete for the agonist binding site, and require higher agonist concentration to elicit a given response.

  • Non-competitive – these bind at a site other than the agonist binding site, or even to a completely different molecular target. The result is the lowering of the maximum possible response in addition to the usual antagonist effect of ‘displacing’ agonist activity to higher concentration.


Case study trial targets

Adrenoceptor and control of cardiac function

Adrenoceptor is receptor for two important hormones: adrenaline (肾上腺素) and noradrenaline (去甲肾上腺素).

Widely distributed, being responsible for control of the stimulation and relaxation of muscle, including the heart.

Mediate the control of cardiac function by the sympathetic nervous system; the parasympathetic nervous system control is mediated by muscarinic acetylcholine receptors.

Remember that cytoplasmic [Ca2+] regulates the development of tension in muscles, such as the heart.


Case study trial targets

Adrenoceptor and control of cardiac function

  • The activation of and adrenoceptors usually elicits opposing responses:

  •  receptor activation leads to constriction of veins and arterioles.

  •  receptor activation leads to dilation of veins and arterioles.


Function of adrenoceptors in heart & vascular system trial targets

  • Epinephrine administered rapidly intravenously has a number of simultaneous effects that contribute to a rapid rise in blood pressure on its administration.

  • A rise in the strength of ventricular contraction (a positive inotropic action)

  • The heart rate is increased (a positive chronotropic action)

  • Blood vessels become constricted.

  • Noting the opposing roles of  and  receptors, it may be no surprise to discover that administration regimes other than rapidly intravenous injection can have quite different effects.


trial targets1 and 2-adrenoceptor’s activation leads to constriction of vascular smooth muscle

1 and 2-adrenoceptor’s activation leads to Ca2+ influx, relaxation of vascular smooth muscle, so enhances contraction and increase heart rate.

3 and 4-adrenoceptor’s presence in heart is not fully established, and their role is even more uncertain.


trial targets1-adrenoceptor agonists

Treat hypotension through vasoconstriction, leading to increased blood pressure. Also valuable adjuncts to local anaesthetics, as vasoconstriction can slow the systemic dispersal of the anaesthetic.

Drugs in this class include:




trial targets2-adrenoceptor agonists

Treat hypertension, through action at the CNS, reducing signal to the heart and so lowering cardiac activity and constriction of the peripheral vasculature.

Drugs in this class include:




trial targets-adrenoceptor agonists

Treat hypotension, cardiac arrhythmias & cardiac failure. Stimulate the rate and force of cardiac contraction, and lead to a drop in peripheral vascular resistance.

Drugs in this class include:




trial targets1-Adrenoceptor antgonists

Inhibiting the action of endogenous vasoconstrictors, resulting in vasodilation of both arteries and veins, and thus reduction of blood pressure. Treating hypertension and cardiac failure.

Drugs in this class include:




trial targets2-Adrenoceptor antgonists

Just as 2-adrenoceptor agonists unexpectedly reduce vasoconstriction and lower cardiac activity, their antagonists cause a rise in blood pressure.

Yohimbine is an 2- adrenoceptor antagonist.



trial targets-Adrenoceptor antgonists

Treating hypertension, angina and ischemic heart disease, also cause an increase in peripheral resistance to blood flow, although this effect is reversed on prolonged administration.

Drugs in this class include:




Any questions? Thank you! trial targets