Drug Design - A Review

Abstract

Pharmaceutical drug discovery is an expensiveand timeconsuming process.Thedevelopmentofadrugfromaninitialideatoitsentryintothemarketisaverycomplex processwhichcantakearound5-10yrs.andcostisvery highuptobillion.Itisan developmentprocessinvolvesuseof variety of computationaltechniques,such as structureactivity relationship,quantitativestructureactivity relationship,molecular mechanics,quantam mechanics,moleculardynamicsand drug protein docking. The ideaforanewdevelopmentcancomefromavarietyofsourceswhichincludethe currentnecessitiesofthemarket,newemergingdiseases,academicandclinical research,commercialsector.Thepharmaceuticalindustryisunderpressurein developingcosteffectivenessdrugmoleculefromthepreviousknowledgeand establishedQuantitativeStructureActivityRelationships.Thestructurebaseddesignis oneof reliableandpromisingtechniquesusedindrugdesigning.Indrugdesign,the mainaimisto?ndoutthethreedimensionalstructureof pharmacologically signi?cant receptorligandcomplexes.Theaimofthisreviewistogiveanoverviewontherational drugdesign approacheswith a casestudy on drugdiscovery forin?uenza Avirus,HER2Receptor,targetingdopamineD3receptor,purpose,andapplicationsofQSAR. Thisarticlehighlightthebene?tsandpromisesofdevelopingtoolsfordrugdiscovery.

Introduction

Overview of Drug Design

Drug design is an integrated scientific process aimed at creating "tailored drugs" that interact specifically with biological targets. It heavily uses computational methods such as:

• Structure-Activity Relationship (SAR)

• Quantitative Structure-Activity Relationship (QSAR)

• Molecular mechanics & dynamics

• Quantum mechanics

• Protein-ligand docking

Drug behavior in the body (biosynthesis region) influences its action—positive (therapeutic) or negative (toxic). Drug design is often done through Computer-Aided Drug Design (CADD), which includes structure-based and ligand-based methods.

Lipinski's Rule of Five (Drug-likeness Criteria)

A drug is likely to be orally active if it has:

1. ≤ 5 hydrogen bond donors

2. ≤ 10 hydrogen bond acceptors

3. Molecular mass < 500 Daltons

4. logP (partition coefficient) ≤ 5

Docking

Docking simulates the binding of a small molecule (ligand) to a target protein:

• Molecular Docking: Predicts best-fit, non-covalent complex formation.

• Blind Docking: Done without prior knowledge of the active site.

• Direct Docking: Uses known active site from X-ray or NMR data. Requires accounting for pH, cofactors, and conformational changes.

QSAR (Quantitative Structure–Activity Relationship)

QSAR correlates chemical structure with biological activity using statistical models, often employing multiple regression analysis.

• Main determinants: Lipophilicity, electronic effects, and steric properties.

• Hansh Analysis: Divides drug action into transport and binding stages, and uses mathematical models to predict activity.

• Applications:

  • Predict activity of new compounds

  • Optimize lead compounds

  • Understand drug-receptor interactions

• Limitations: Biological data inconsistency, multiple modes of action, and statistical limitations.

CADD (Computer-Aided Drug Design)

CADD accelerates drug discovery using computational tools to:

• Reduce cost and time

• Virtually screen compounds

• Identify molecular targets

• Perform simulations

Two Major Types:

1. Structure-Based Drug Design (SBDD): Requires 3D protein structure; uses molecular docking and dynamics.

2. Ligand-Based Drug Design (LBDD): Used when protein structure is unknown; analyzes ligands to find common features influencing activity.

Pharmacophore: An abstract model identifying key steric and electronic features necessary for biological activity.

ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity)

ADMET models predict a compound’s pharmacokinetics and toxicity, helping filter out unsuitable candidates early. Advanced machine learning tools assist in:

• Calculating physicochemical properties

• Evaluating medicinal chemistry rules

• Predicting ADME and toxicity endpoints

Also mentions ADMET polymerization, used in synthetic chemistry with catalysts (e.g., Schrock and Grubbs).

Chemical Structure Drawing

Different representations used in organic chemistry include:

• Kekulé structures

• Condensed formulas

• Skeletal formulas (line-bond structures)

Objectives include converting between structural formats and determining molecular formulas.

Conclusion

Drugdesign isthecreativeprocessof ?ndingnewremediesbasedon theknowledgeof biological targetThisreview discussesprincipleof drug design,variousapproachesof drugdesign,leaddiscovery,leadmodi?cationandvarioustypesofdrugdiscovery.Bio- isosterism isan importantlead modi?cation approach thathasbeen shown tobe usefultoattenuatetoxicityortomodifytheactivityofalead,andmayhavea signi?cantroleinthealterationofpharmacokineticsofalead.

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Copyright

Copyright © 2025 Anita Jadhav , Bhagyashree G. Dhotre, Dipali Jawale , Vaishnavi Bhosale , Kalyani Bodkhe . This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.