- To predict the absorption and distribution properties of small chemical drug like compounds.
A molecule is formed when two or more atoms are combined together chemically (e.g. H2). A compound is said to be a molecule when it contains at least two different elements (e.g. H2O). All compounds can be called as molecules but all molecules are not compounds. In terms of pharmacology or in biochemistry, a small molecule is an organic compound which has low molecular weight that may act as a substrate or inhibitor. In medical field, the term is restricted to the molecule that binds to a biopolymer and act as an effector. Most of the small molecules are drug molecules.
Drug molecules are potential lead molecules which act as therapeutic agents and gives beneficiary effects. To come up with single potential lead molecule, it takes 12 -16 years. Besides the beneficiary aspects, there may be adverse effects also when using drug/potential lead molecules.
If the drug is unable to reach its target organ at a sufficient concentration, the observed molecule will fail in the clinical trials due to lack of its therapeutic effect. The drugs to be synthesized must meet certain requirements to cross through the clinical tests. Successful drug molecules must be able to go through several tests like absorption, distribution, metabolism, elimination/excretion and toxicity. Adsorption test is done to check for the amount of drug properly absorbed. After absorption, it should be distributed within the body, such as blood and lymphatic vessels to reach its organ with sufficient concentration. Ability of drug molecules to reach its target should be also considered which is done by metabolism and elimination tests. Metabolism is the process in which the body breaks down the small molecules by degrading in the liver with the enzymes. Elimination is the other process in which drug is eliminated through kidney or faeces. Thus pharmacokinetic properties are very much important for synthesis of a drug molecule.
Pharmacokinetics is the way how body acts when the drug is administered. Pharmacokinetics measure the rate of Absorption, Distribution, Metabolism and Elimination/Excretion.
The movement of a molecule from the site of administration to the target site is absorption. Small drug molecules can diffuse through the membranes faster and easier than the larger molecules. Most of the drugs are passively absorbed but some of them needs carrier to transport.
Basic drugs will be absorbed better in the intestine, whereas the acidic drugs will be absorbed in stomach. The surface area of intestine is much bigger compared to stomach, so this might be a reason for most of the absorption of a drug takes place in small intestine. Drugs which are amphipathic does not have any issues in case of absorption. Some drugs which are insoluble in water float as globules in the intestine and bile salts emulsify these compounds into smaller particles. The drugs which are administered into subcutaneous layer or muscle are absorbed into the circulatory system through the small pores in the capillary walls. The absorption of drugs administered orally depends on the dissolution of compounds in the aqueous content of gastrointestinal (GI) tract which are then mediated through barriers of the GI tract to reach blood.
Factors affecting absorption:
a) Physiochemical property of a drug.
b) Dosage form.
c) Physiological and pathological variables (e.g. blood flow, Ph, effect of food and other drugs).
When a medication is administered intravenously, its bioavailability is 100 %. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient.
The movement of drugs throughout the body can be determined by blood flow through the tissues. When the drug is absorbed by GI tract, the hepatic portal system plays a major role in distribution. Most of the drugs taken by hepatic system are stored and may be metabolized before reaching the rest of the body. So, the drugs that are metabolized by enzymes in liver have a high risk when administered orally due to high hepatic first pass.
The distribution of drug is carried out with binding proteins in plasma and through the lipophilic nature of drugs carried through blood brain barrier.
Plasma protein binding
Insoluble substances are transported through blood by binding to proteins which are amphipathic in structure. The lipophilic compounds are attached to lipophilic group of proteins and they are loosely bound. In plasma, the drugs are partly bound to protein and partly in solution i.e. drug exists in two forms: bound and unbound. The protein bound form is in equilibrium with free drug. When the free unbound proportion of a drug reaches to target, the bound portion of a drug will be released from plasma protein to maintain equilibrium.
Blood Brain Barrier
In central nervous system, the capillaries have pores sealed by connective tissue, so only small molecules can cross the blood brain barrier. These small molecules that cross the blood brain barrier should be very lipophilic in nature. This barrier is the only protective layer of central nervous system and avoids some drugs crossing CNS and causing adverse effects.
Most of the drugs fail in clinical trials, so researchers or pharmaceutical companies have come up with computer based methods to predict drug likeness by ADME-tox test for a given molecule. There are several such tools to predict properties of a drug molecule, some of them are commercial, some are online web servers and few of them are freely downloadable.
PreADMET is one of the online resources to predict ADME, toxicity, Drug likeness and molecular descriptor calculation.
The input can be given to PreADMET tool is either by drawing the molecule or by uploading the “mol” format of the compound. The compound’s structure or the “mol” format can be obtained from the different chemical databases like Drug bank, chEMBL, Pubchem, etc.
PreADMET tools uses the strategy to obtain the model which can be used to predict absorption and distribution
The strategy steps used are described below.
1. Take a set of compounds, calculate molecular descriptors for all compounds.
2. The set of compounds can be divided into training , validation , and external dataset using principal component analysis and cell based compounds selection.
3. To get most promising dataset, filter the molecular descriptors.
4. Use Genetic Functional Approximation (GFA) to find the best descriptors set for a training set . Information regarding GFA algorithm can be obtained
5. Batch run Rprop neural net using descriptors in op neural net in each equation obtained by GFA learning
6. The model having minimum RMSE is choosen as the best model in both training and validation sets
7. Thus evaluate the performance of trained artificial neural network
8. Validate the final model using external dataset for testing.