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ADVANCES IN COMPUTER AIDED DRUG DESIGN

Abstract

Key words

In the early ages of drug design and discovery system, very less information was available with respect to the structure of ligands and the targets. With advancement in the technological and information system now it is possible to simulate the drug-target interactions inside the computer chips. Computer-aided drug design (CADD) is a modern, rationale and diverse discipline where various aspects of basic and applied knowledge are used to design new drugs. There are different strategies, protocols and algorithms included under computer aided drug design. It is the researcher who can choose the perfect Strategy for CADD depending on the extent of structural and other information available regarding the targets (enzyme/receptor) and the ligands. In the present review we reported a brief history of CADD together with its progress in the last few years.

CADD, Structure Based Drug Design, Molecular Modelling, Docking.

ARTICLE INFO:Article history:Received: 01 August 2015Received in revised form:09 September 2015Accepted: 1 November 2015Available online: 10 November 2015

Jun Moni KalitaDepartment of Pharmaceutical ChemistryHimalayan Pharmacy InstituteMajhitar, E-Sikkim-737136, INDIAE-mail: pjmk84@gmail.comPhone: +919508980893

and its commercialization is a tedious and time consuming process and moreover the cost has increased drastically during the past thirty-four years. In 1962, the total cost was $4 million, which became $350 million in 1996. It has been observed that only small amount of drugs which has been synthesized will be examined in clinics and among them few will be marketed. In 1950, it has been estimated that about 7000 compounds are isolated or synthesized and then tested for therapeutic activity for each one that became a pharmaceutical product. The challenge is becoming more difficult when 10,000 compounds had to be evaluated in 1979, and this number could be as high as 20,000 today [1, 2]. So, due to this reason now the entire world's major pharmaceutical and biotechnology

The discovery of a drug, its development

INTRODUCTION

companies started using computational design tools. These tools are used to replace the crude mechanical models by displaying of structure which is a much more accurate reflection of molecular reality capable of demonstrating motion and solvent effects [3]. Apart from this, theoretical calculations permit the computation of free binding energies and other relevant molecular properties. The term "molecular modelling" has expanded over the last decades from a tool to visualize three dimensional (3D) molecular structures & to simulate, predict & analyze the properties and behaviour of molecules on an atomic level to a data-mining & in-silico drug design platform to organize many compounds & their properties into databases & to perform virtual drug screening via 3D database searches for novel drug compounds [3-5].

Jun M Kalita*, Ashmita Saha, Dipankar Nath, Uddhav Patangia

Department of Pharmaceutical Chemistry, Himalayan Pharmacy Institute, Majhitar, Rangpo, E. Sikkim - 737136, INDIA

Corresponding Author:

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In the past few years, the field of computer-aided drug design (CADD) has grown speedily, enhancing the perceptive of multifaceted and difficult biological processes. With the help of computer programs, it is now possible to study and predict experimental results with sound accuracy in

a short duration making it both cost and time effective. In the recent few decades computational methods has been extensively used in the field of drug design and discovery. Few examples of drugs as a result of computer aided drug design are included in table 1 [6].

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Table 1: Examples of drugs found with the help of CADD

Year

1989

1997

1998

1999

2007

Drug Name

Zanamivir

Nelfinavir

Raltitrexed

Amprenavir

Raltegravir

Used as

Anti HIV

Anti HIV

Anti Cancer

Anti HIV

Anti HIV

Figure 1: Work flow of computer aided drug design

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Though the total energy has no physical meaning by itself, but differences in total energy between two different conformations of the same molecule can be compared[9-11].

Quantum mechanics

It determines the complete structural information by considering the molecule up to atomic and electronic level. As its calculation are much complex in nature, quantum mechanical methods are restricted to simple system & the approximation known as molecular orbital theory is mostly used for practical purposes [11].

Virtual Screening

Virtual screening (VS) is a computational technique used in drug design and discovery to search library of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme. These virtual screening techniques can be broadly grouped in two group viz. ligand-based virtual screening and structure based or target-based virtual screening. Methods like pharmacophore modelling and QSAR comes under ligand based virtual screening where else method like docking comes under structure based or target based drug design.

Pharmacophore modelling

A pharmacophore is an abstract description of molecular properties which are necessary for molecular recognition of a ligand by a biological macromolecule . The IUPAC def ines a pharmacophore to be "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response". A typical pharmacophore features include hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors, cations, and anions.

A pharmacophore model explains how structurally diverse ligands can bind to a common receptor site. In addition pharmacophore models can be used to identify and screen newly designed molecules for their capability to bind with the same target protein. These pharmacophoric points may be located on the ligand itself or may be projected points presumed to be located in the receptor [12].

Molecular Modelling

Molecular modelling comprises all theoretical and computational methods used to model or mimic the behaviour of small molecules like protein, DNA, ligand etc. These molecular modelling techniques are used in the fields of computational chemistry, drug design, computational biology and materials science for studying different molecular systems. The simplest calculations can be done manually by hand, but computers are required to perform the modelling and complex calculations of any bigger sized systems. The common feature of molecular modelling techniques is the atomistic level description of the molecular systems. This may include treating atoms as the smallest individual unit (the Molecular mechanics approach), or explicitly modelling electrons of each atom (the quantum chemistry approach) [7, 8].

Molecular mechanics

Molecular mechanics considers a molecule to be a compilation of masses interacting with each other through harmonic forces. Thus the atoms in molecules are treated as ball of different sizes and joined together by springs of variable strengths and equilibrium distances (bonds).This simplification enables molecular mechanics as a fast computational model that can be applied to molecules of any size. The total energy of molecule is calculated by adding the different contributions that compute the deviations from equilibrium of bond lengths, angles and torsions plus non-bonded interactions as show in equation I.

E = E + E + E + E + E (I)tot str bend tors vdw ele

Where E refers to total energy of the molecule, E tot str

refers to the bond stretching energy term, E is the bend

angle bending energy term, E is the torsional tors

energy term, E is the van der waals energy term vdw

and E is the electrostatic energy term.elec

The equilibrium values of these bond lengths and bond angles are the corresponding force constants used in the potential energy function defined in the force fields and define a set known as force field parameters. Each deviation from these equilibrium values will result in increasing total energy of the molecule. So, the total energy is a measure of intra molecular strain relative to a hypothetical molecule with an ideal geometry of equilibrium.

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QSAR

Quantitative Structure Activity Relationship

(QSAR) modelling is the construction of

extrapolative models of pharmacological activities

as a function of structural and molecular

information of a compound library. The idea of

QSAR has normally been used for drug discovery

and development and has gained wide applicability

for correlating molecular information with not only

biological activities but also with other

physicochemical properties, which has therefore

also been termed as Quantitative Structure Property

Relationship (QSPR). Molecular parameters that

are used to contribute for electronic properties,

hydrophobicity, steric effects, and topology can be

determined empirically by experimentation or

theoretically via computational chemistry. A given

collection of data sets is then subjected to data pre-

processing and data modelling through the use of

statistical and/ or machine learning techniques.

Quantitative structure-activity relation- ship

(QSAR) and quantitative structure- property

relationship (QSPR) made it feasible to forecast the

activities/properties of a given compound as a

function of its molecular substituent. By this new

and untested compounds having similar molecular

features as compounds used in the construction of

QSAR/QSPR models are likewise supposed to also

possess similar activities/properties. A number of

successful QSAR/QSPR models have been

published in the last few years which include a wide

span of biological and physicochemical properties.

QSAR/QSPR has gained a great popularity in the

field of drug design and discovery [13].

Docking

Molecular Docking is the study of ability of a ligand

to fit with a receptor or protein. It is a problem like

solving a three dimensional puzzle. It is a method

which predicts the favoured orientation of a

molecule to other when bound to each other to form

a stable complex. Taking the knowledge of the

preferred orientation, strength of association or

binding affinity between two molecules is predicted.

It is often used to guess the binding strength of small

molecule like drug candidates to their protein targets

in order to in turn predict the affinity and activity of

the small molecule. Hence docking plays a very

important role in the era of rational design of drugs.

Molecular docking is a problem of "lock-and-key"

type, where one finds the right relative orientation of

the "key" which opens the "lock". Here, the protein

is thought of as the "lock" and the ligand is thought

of as a "key". Molecular docking may be explained

as an optimization problem, which describes the

"best-fit" orientation of a ligand that binds to a

particular protein. The point up of molecular

docking is to computationally simulate the

molecular recognition process. The main aim of

molecular docking technique is to reach an

optimized conformation for both the protein and

ligand and relative orientation between protein and

ligand with an energy minimized system [14-15].

CONCLUSION

Finally it can be concluded that, the primary goal in

drug design is to predict whether a given molecule

will bind to a target and if so how strongly. Computer

Aided Drug Design, which is the center of attraction

in the modern era of drug design and discovery, can

be also said as rational method of drug design and

discovery.

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