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In silico identification of inhibitors against Plasmodium falciparum histone deacetylase 1 (PfHDAC-1)

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Abstract

In erythrocytes, actively multiplying Plasmodium falciparum parasites exhibit a unique signature of virulence associated histone modifications, thereby epigenetically regulating the expression of the majority of genes. Histone acetylation is one such modification, effectuated and maintained by the dynamic interplay of two functionally antagonist enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Their inhibition leads to hypo/hyperacetylation and is known to be deleterious for P. falciparum, and hence they have become attractive molecular targets to design novel antimalarials. Many compounds, including four Food and Drug Administration (FDA) approved drugs, have been developed so far to inhibit HDAC activity but are not suitable to treat malaria as they lack selectivity and cause cytotoxicity in mammalian cells. In this study, we used comparative modeling and molecular docking to establish different binding modes of nonselective and selective compounds in the PfHDAC-1 (a class I HDAC protein in P. falciparum) active site and identified the involvement of active site nonidentical residues in binding of selective compounds. Further, we have applied virtual screening with precise selection criteria and molecular dynamics simulation to identify novel potential inhibitors against PfHDAC-1. We report 20 compounds (10 from ChEMBL and 10 from analogues compound library) bearing seven scaffolds having better affinity toward PfHDAC-1. Sixteen of these compounds are known antimalarials with 14 having activity in the nanomolar range against various drug resistant and sensitive strains of P. falciparum. The cytotoxicity of these compounds against various human cell lines are reported at relatively higher concentration and hence can be used as potential PfHDAC-1 inhibitors in P. falciparum. These findings indeed show great potential for using the above molecules as prospective antimalarials.

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Abbreviations

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitors

PfHDCA-1:

Plasmodium falciparum HDAC 1

HsHDAC-1:

Homo sapiens HDAC 1

HsHDAC-2:

Homo sapiens HDAC 2

HsHDAC8:

Homo sapiens HDAC 8

HTVS:

High throughput virtual screening

nM:

Nanomole

μM:

Micromole

ns:

Nanoseconds

ps:

Picoseconds

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Acknowledgments

We acknowledge Indian funding agencies DBT-COE, University Potential of Excellence (UPE-II, ID 28) by UGC, and DST-PURSE for their financial support. We wish to thank Schrödinger’s team India for providing three months academic license. Prof. Pradipta Bandyopadhyay, SCIS, JNU is acknowledged for allowing us to use AMBER16 package. AK acknowledges the Council of Scientific and Industrial Research (CSIR), India for providing scholarship.

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  1. School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Amarjeet Kumar & Naidu Subbarao

  2. Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India

    Suman Kumar Dhar

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  1. Amarjeet Kumar
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Work design and conceptualization was done by AK, SKD, and NS. All the work was carried out by AK. Data analysis AK and NS. The manuscript was prepared and written by AK, SKD, and NS.

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Correspondence to Naidu Subbarao.

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Kumar, A., Dhar, S.K. & Subbarao, N. In silico identification of inhibitors against Plasmodium falciparum histone deacetylase 1 (PfHDAC-1). J Mol Model 24, 232 (2018). https://doi.org/10.1007/s00894-018-3761-1

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