Muhammed Mujahed
Master’s of Science in Biotechnology.
SRTM University.

Drug design is an integrated developing discipline which portends an era of ‘tailored drug’. It involves the study of effects of biologically active compounds on the basis of molecular interactions in terms of molecular structure or its physico-chemical properties involved. It studies the processes by which the drug produce their effects, how they react with the protoplasm to elicit a particular pharmacological effect or response how they are modified or detoxified, metabolized or eliminated by the organism.

Disposition of drugs in individual region of biosystems is one of the main factors determining the place , mode and intensity of their action . The biological activity may be “positive” as in drug design or “negative” as in toxicology. Thus drug design involves either total innovation of lead  or an optimization of already available lead. These concepts are the building stones up on which the edifice of drug design is built up.

The drug is most commonly an organicsmall  molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is often referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.


Principles of Drug Design

Lipinski’s Rule of Fives
Lipinski's rule of five
also known as the Pfizer's rule of five or simply the Rule of five (RO5) is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A. Lipinski in 1997, based on the observation that most medication drugs are relatively small and lipophilic molecules.

The rule describes molecular properties important for a drug's pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion("ADME"). However, the rule does not predict if a compound is pharmacologically active.

The rule is important to keep in mind during drug discovery when a pharmacologically active lead structure is optimized step-wise to increase the activity and selectivity of the compound as well as to insure drug-like physicochemical properties are maintained as described by Lipinski's rule. Candidate drugs that conform to the RO5 tend to have lower attrition rates during clinical trials and hence have an increased chance of reaching the market

Components of the rule :
Lipinski's rule states that, in general, an orally active drug has no more than one violation of the following criteria:

  • Not more than 5 hydrogen bond donors (nitrogen or oxygenatoms with one or more hydrogenatoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygenatoms)
  • A molecular mass less than 500 daltons
  • An octanol-water partition coefficient log P not greater than 5

Note that all numbers are multiples of five, which is the origin of the rule's name. As with many other rules of thumb, (such as Baldwin's rules for ring closure), there are many exceptions to Lipinski's Rule.

Pharmacokinetics of  drug design :

• Drugs must be polar - to be soluble in aqueous conditions

to interact with molecular targets

• Drugs must be ‘fatty’ - to cross cell membranes

to avoid rapid excretion

• Drugs must have both hydrophilic and lipophilic characteristics

• Many drugs are weak bases with pKa ’s 6-8.


The various approaches used in drug design include the following..
1) Random screening of synthetic compounds or chemicals and natural products by bioassay procedures.
2) Novel compounds preparation based on the known structures of biologically active, natural substances of plant and animal origin, i.e., lead skeleton.
3) Preparation of structural analogs of lead with increasing biological activity and
4) Application of bioisosteric principle.

The current trend in the drug design is to develop new clinically effective agents through the structural modification of lead nucleus. The lead is a prototype compound that has the desired biological or pharmacological activity but may have many undesirable characteristics, like high toxicity, other biological activity, insolubility or metabolism problems. Such organic leads once identified, are easy to exploit. This process is rather straightforward. The real test resides with the identiication of such lead real test resides with the identification of such lead bioactive positions on the basic skeleton of such leads.

Methods of lead Discovery:

Random Screening:
In the absence of known drugs and other compounds with desired activity, a random screen is a valuable approach. Random screening involves no intellectualization; all compounds are tested in the bioassay without regard to their structures.

The two major classes of materials screened are synthetic chemicals and natural products (microbial, plant, and marine).


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