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Structure-Based Drug Design of PfDHODH Inhibitors as Antimalarial Agents

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Structural Bioinformatics: Applications in Preclinical Drug Discovery Process

Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 27))

Abstract

Structure-based drug design (SBDD) is being efficiently used for the design of antimalarial agents. It is a very effective tool for challenges like drug selectivity and resistance. Over the past decade, a considerable number of druggable targets have been explored—these include Na+ ATPase 4 ion channel, cytochrome bc1, mitochondrial electron transport chain, phosphatidylinositol 4-kinase (PfPI4 K), dihydroorotate dehydrogenase , hemozoin formation, dihydrofolate reductase inhibitors, etc. Among these, Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a new and very promising target. PfDHODH has shown considerable potential in arresting growth of the parasite at blood stage by inhibiting pyrimidine biosynthesis . This chapter provides a review of all the SBDD efforts for the development of inhibitors against PfDHODH.

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Abbreviations

ACT:

Aspartate carbamoyltransferase

ADME:

Absorption, distribution, metabolism, and excretion

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity index analysis

CoQ:

Coenzyme Q (Ubiquinone)

CTP:

Cytidine triphosphate

DBP:

Docking-based pharmacophore

DHOtase:

Dihydroorotase

DHO:

Dihydroorotate

DHODH:

Dihydroorotate dehydrogenase

dTMP:

Deoxyribose thymidine monophosphate

E. coli.:

Escherichia coli

FAD:

Flavin adenine dinucleotide

FMN:

Flavin mononucleotide

G/PLS:

Genetic partial least squares

GAT/CPS:

Glutamine amidotransferase/carbamoyl phosphate synthetase

m-:

meta-

MM/GBSA:

Molecular mechanics/Generalized Born surface area

MSA:

Molecular shape analysis

MLR:

Multilinear regression

NAD:

Nicotinamide adenine dinucleotide

OMPDC:

Orotidine 5′-monophosphate decarboxylase

OPRT:

Orotate phosphoribosyltransferase

ORO:

Orotate

o-:

ortho-

p-:

para-

Pb :

Plasmodium berghei

PDB:

Protein Data Bank

Pf :

Plasmodium falciparum

PRPP:

Phosphoribosylpyrophosphate

QSAR:

Quantitative structure–activity relationship

RMS:

Root mean square

RNA:

Ribonucleic Acid

SBDD:

Structure-based drug design

SVM:

Support vector machine

UMP:

Uridine monophosphate

UTP:

Uridine triphosphate

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Acknowledgements

The University Grants Commission is gratefully acknowledged for the financial support to Shweta Bhagat (UGC, Grant No. 43395). The authors thank Department of Science and Technology (DST), Government of India, New Delhi, India, for financial support.

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India

    Shweta Bhagat & Prasad V. Bharatam

  2. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, 160062, Punjab, India

    Anuj Gahlawat

Authors
  1. Shweta Bhagat
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  2. Anuj Gahlawat
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  3. Prasad V. Bharatam
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Correspondence to Prasad V. Bharatam .

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Editors and Affiliations

  1. Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, India

    C. Gopi Mohan

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Bhagat, S., Gahlawat, A., Bharatam, P.V. (2019). Structure-Based Drug Design of PfDHODH Inhibitors as Antimalarial Agents. In: Mohan, C. (eds) Structural Bioinformatics: Applications in Preclinical Drug Discovery Process. Challenges and Advances in Computational Chemistry and Physics, vol 27. Springer, Cham. https://doi.org/10.1007/978-3-030-05282-9_6

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