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Design of Novel Dual-Target Hits Against Malaria and Tuberculosis Using Computational Docking

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Multi-Target Drug Design Using Chem-Bioinformatic Approaches

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

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Abstract

Drugs which are purposefully designed to hit more than one target (multi-target drugs) promise a better safety profile and low resistance probability. Multi-target therapy also offers a cost-effective model for pharmaceutical R&D, making it quite an appealing strategy in the domain of neglected tropical diseases (NTDs) and other infections/coinfections of the global impact such as malaria, tuberculosis, and AIDS. We reviewed herein different approaches (knowledge base and screening base) for designing multi-target inhibitors with the special emphasis on the research work of the authors. Additionally, a step-by-step guide (protocol) and different computational resources are also discussed in detail to design multi-target hits for malaria and tuberculosis.

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Abbreviations

2D:

Two dimensional

3D:

Three dimensional

ACD:

Advanced Chemistry Development, Inc.

ADMET:

Absorption, distribution, metabolism, excretion, and toxicity

ADT:

AutoDock Tool

AIDS:

Acquired immune deficiency syndrome

AM1:

Austin model 1

AMBER:

Assisted model building with energy refinement

AMR:

Antimicrobial resistance

BE:

Binding energy

BMRB:

Biological magnetic resonance data bank

CCDC:

The Cambridge Crystallographic Data Centre

CHARMM:

Chemistry at Harvard Macromolecular Mechanics

ChEMBL or ChEMBLdb:

Chemical database of bioactive molecules with drug-like properties

COX:

Cyclooxygenase

DHFR:

Dihydrofolate reductase

DMEs:

Disease-modifying agents

DMLs:

Designed multiple ligands

DSV:

Discovery Studio Visualizer

DUD:

Directory of useful decoys

EGFR:

Epidermal growth factor receptor

EMBL-EBI:

European Bioinformatics Institute

FDA:

Food and Drug Administration, USA

GA:

Genetic algorithm

HIV:

Human immunodeficiency virus

In silico (syn in computo):

Performed on computer

LE:

Ligand efficiency

LGA:

Lamarckian genetic algorithm

LS:

Local search

MAPK:

Mitogen-activated protein kinase

MD:

Molecular dynamics

MDR:

Multidrug resistance

MGLTools:

Molecular Graphics Laboratory tools

MM2:

Molecular mechanics 2

MMV:

Molegro Molecular Viewer

MTDs:

Multi-target drugs

MW:

Molecular weight

NSAIDs:

Nonsteroidal anti-inflammatory drugs

NTDs:

Neglected tropical diseases

OMICS:

Genomics, proteomics, or metabolomics

PAINS:

Pan-assay interference compounds

PDB:

Protein Data Bank

PM3:

Parameterized model number 3

QSAR:

Quantitative structure activity relationship

R&D:

Research and development

RCSB:

Research Collaboratory for Structural Bioinformatics

RMSD/rmsd:

Root-mean-square deviation

SA:

Simulated annealing

SHAFTS:

Shape-Feature Similarity

SITITCH:

Search tool for interacting chemicals

STRING:

Search tool for the retrieval of interacting genes/proteins

TB:

Tuberculosis

TCM:

Traditional Chinese medicines

TDR:

Total drug resistance

TS:

Thymidylate synthase

TTD:

Therapeutic target database

WT:

Wild type

XRD:

Extreme drug resistance

ZINC:

Zinc Is Not Commercial (ZINC database)

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Acknowledgments

The authors gratefully acknowledge Science and Engineering Research Board (SERB), Govt. of India (Grant No. SER-892-CMD), to financially assist this work.

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Authors and Affiliations

  1. Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

    Manoj Kumar & Anuj Sharma

  2. Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada

    Manoj Kumar

Authors
  1. Manoj Kumar
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  2. Anuj Sharma
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Correspondence to Anuj Sharma .

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Editors and Affiliations

  1. Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India

    Kunal Roy

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Kumar, M., Sharma, A. (2018). Design of Novel Dual-Target Hits Against Malaria and Tuberculosis Using Computational Docking. In: Roy, K. (eds) Multi-Target Drug Design Using Chem-Bioinformatic Approaches. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/7653_2018_22

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  • DOI: https://doi.org/10.1007/7653_2018_22

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8732-0

  • Online ISBN: 978-1-4939-8733-7

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