Network Pharmacological Analysis through a Bioinformatics Approach of Novel NSC765600 and NSC765691 Compounds as Potential Inhibitors of CCND1/ CDK4/ PLK1/ CD44 in Cancer Types

Ntlotlang Mokgautsi; Yu-Chi Wang; Bashir Lawal; Harshita Khedkar; Maryam Rachmawati Sumitra; Alexander T H Wu; Hsu-Shan Huang

doi:10.3390/cancers13112523

Network Pharmacological Analysis through a Bioinformatics Approach of Novel NSC765600 and NSC765691 Compounds as Potential Inhibitors of CCND1/ CDK4/ PLK1/ CD44 in Cancer Types

Cancers (Basel). 2021 May 21;13(11):2523. doi: 10.3390/cancers13112523.

Authors

Ntlotlang Mokgautsi^{1

2}, Yu-Chi Wang³, Bashir Lawal^{1

2}, Harshita Khedkar^{1

2}, Maryam Rachmawati Sumitra^{1

2}, Alexander T H Wu^{4

5

6

7}, Hsu-Shan Huang^{1

2

7

8

9}

Affiliations

¹ PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.
² Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
³ Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.
⁴ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁵ The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁶ Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
⁷ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan.
⁸ School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan.
⁹ PhD Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.

Abstract

Cyclin D1 (CCND1) and cyclin-dependent kinase 4 (CDK4) both play significant roles in regulating cell cycle progression, while polo-like kinase 1 (PLK1) regulates cell differentiation and tumor progression, and activates cancer stem cells (CSCs), with the cluster of differentiation 44 (CD44) surface marker mostly being expressed. These oncogenes have emerged as promoters of metastasis in a variety of cancer types. In this study, we employed comprehensive computational and bioinformatics analyses to predict drug targets of our novel small molecules, NSC765600 and NSC765691, respectively derived from diflunisal and fostamatinib. The target prediction tools identified CCND1/CDK4/PLK1/CD44 as target genes for NSC765600 and NSC765691 compounds. Additionally, the results of our in silico molecular docking analysis showed unique ligand-protein interactions with putative binding affinities of NSC765600 and NSC765691 with CCND1/CDK4/PLK1/CD44 oncogenic signaling pathways. Moreover, we used drug-likeness precepts as our guidelines for drug design and development, and found that both compounds passed the drug-likeness criteria of molecular weight, polarity, solubility, saturation, flexibility, and lipophilicity, and also exhibited acceptable pharmacokinetic properties. Furthermore, we used development therapeutics program (DTP) algorithms and identified similar fingerprints and mechanisms of NSC765600 and NSC765691 with synthetic compounds and standard anticancer agents in the NCI database. We found that NSC765600 and NSC765691 displayed antiproliferative and cytotoxic effects against a panel of NCI-60 cancer cell lines. Based on these finding, NSC765600 and NSC765691 exhibited satisfactory levels of safety with regard to toxicity, and met all of the required criteria for drug-likeness precepts. Currently, further in vitro and in vivo investigations in tumor-bearing mice are in progress to study the potential treatment efficacies of the novel NSC765600 and NSC765691 small molecules.

Keywords: bioinformatics; cancer stem cells (CSCs); drug resistance; drug-likeness; pharmacokinetics.