Computer Assisted Drug Design

Dr.Keshav Mohan, MSM College,Kayamkulam,Kerala

A drug is any chemical substance that, when absorbed into the body of a living organism, alters normal bodily function. A drug is a chemical substance used in treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. Some interesting classes of drugs are:

• Recreational drugs are chemical substances that affect the central nervous system, such as opioids or hallucinogens. They may be used for perceived beneficial effects on perception, consciousness, personality, and behavior. Some drugs can cause addiction and habituation. These include alcohol, tobacco, betel nut, and caffeine products.

• Drugs that are considered to have spiritual or religious use are called entheogens. Some religions are based completely on the use of certain drugs. Entheogens are mostly hallucinogens, being either psychedelics or deliriants, but some are also stimulants and sedatives.

• Nootropics, or "smart drugs", are drugs that are claimed to improve human cognitive abilities. Nootropics are used to improve memory, concentration, thought, mood, learning, and many others things. Some nootropics are now beginning to be used to treat certain diseases such as attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. They are also commonly used to regain brain function lost during aging.

• Drugs are usually distinguished from endogenous biochemicals by being introduced from outside the organism. For example, insulin is a hormone that is synthesized in the body; it is called a hormone when it is synthesized by the pancreas inside the body, but if it is introduced into the body from outside, it is called a drug

Drug design is the approach of finding drugs by design, based on their biological targets. Typically a drug target is a key chemical molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen.

Computer-assisted drug design uses computational chemistry Tools & Techniques to discover, enhance, or study drugs and related biologically active molecules. Methods used can include simple molecular modeling, using molecular mechanics, molecular dynamics, semi-empirical quantum chemistry methods, ab initio quantum chemistry methods, DFT etc. The purpose of Computational Techniques is to reduce the number of targets @ Lead Molecule for a good drug that otherwise requires expensive and time-consuming synthesis and trialing.

The important terms referred here are:

Lead compound: –They are molecule or Chemical Compounds with pharmacological or biological activity that can be used as a starting point for chemical modifications

to enhance its potency and selectivity.

An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. The ability to alter the activity of a receptor, also known as the agonist's efficacy is a property that distinguishes it from antagonists, a type of receptor ligand which also bind a receptor but which do not alter the activity of the receptor. The efficacy of an agonist may be positive, causing an increase in the receptor's activity or negative causing a decrease in the receptor's activity.

A receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling (or "signal") molecule may attach. •Ligand is a molecule which binds to a receptor and may be a peptide (such as a neurotransmitter), a hormone, a pharmaceutical drug, or a toxin. • When such binding occurs, the receptor goes into a conformational change which ordinarily initiates a cellular response. •However, some ligands merely block receptors without inducing any response (e.g. antagonists). Ligand-induced changes in receptors result in physiological changes which constitute the biological activity of the ligands.

Drug activity results from the molecular binding of one molecule (the ligand) to the pocket (binding site) of another molecule (the receptor). The receptor is usually a protein (or enzyme). Many ligands show significant geometric and chemical complementarity with the binding site Chemical complimentarity & Mobility facilitate drug activity

• Ligands often form hydrogen bonds with the receptor

• “Hydrophobic pockets” can accommodate a hydrophobic group of the ligand

A drug must be able to get to the target. This often involves passing through cell membranes, which are hydrophobic . Chemical complementarity and mobilityof drug molecules also play vital role. Computational techniques can be used to suggest compounds that may interact favourably with the receptor.

Some important tools and techniques used are below.

Force Fields

Molecular Dynamics

Molecular Docking

QSAR

Pharmacophores

The methods can also be looked upon as follows.

Structure-based methods

• - QM/MM (QSite, Jaguar)

• – Docking (Glide and CombiGlide)

• – Core hopping (CombiGlide)

• – MM-GBSA

• • Prime MM-GBSA (Prime)

• • eMBrAcE (MacroModel)

• – Molecular dynamics (Desmond)

• • FEP

• • Thermodynamics of water in binding site (WaterMap)

Ligand-based methods

• – Quantitative structure activity relationships (QSAR) (Canvas & Strike)

• – Pharmacophore-based searching (Phase)

• – Similarity searching (Canvas)

Detailed account of the above methods are discussed in the presentation.

PLEASE SEE THE POWER POINT PRESENTATIONS GIVEN AS ATTACHMENT BELOW.

Acknowledgment: UGC , New Delhi is acknowledged for generous research fund.