Exploring a structural protein-drug interactome for new therapeutics in lung cancer

Xiaodong Peng, Fang Wang, Liwei Li, Khuchtumur Bum-Erdene, David Xu, Bo Wang, Anthony A. Sinn, Karen Pollok, George Sandusky, Lang Li, John Turchi, Shadia Jalal, Samy Meroueh

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The pharmacology of drugs is often defined by more than one protein target. This property can be exploited to use approved drugs to uncover new targets and signaling pathways in cancer. Towards enabling a rational approach to uncover new targets, we expand a structural protein-ligand interactome (http://www.biodrugscreen.org) by scoring the interaction among 1000 FDA-approved drugs docked to 2500 pockets on protein structures of the human genome. This afforded a drug-target network whose properties compared favorably with previous networks constructed using experimental data. Among drugs with the highest degree and betweenness two are cancer drugs and one is currently used for treatment of lung cancer. Comparison of predicted cancer and non-cancer targets reveals that the most cancer-specific compounds were also the most selective compounds. Analysis of compound flexibility, hydrophobicity, and size showed that the most selective compounds were low molecular weight fragment-like heterocycles. We use a previously-developed screening approach using the cancer drug erlotinib as a template to screen other approved drugs that mimic its properties. Among the top 12 ranking candidates, four are cancer drugs, two of them kinase inhibitors (like erlotinib). Cellular studies using non-small cell lung cancer (NSCLC) cells revealed that several drugs inhibited lung cancer cell proliferation. We mined patient records at the Regenstrief Medical Record System to explore the possible association of exposure to three of these drugs with occurrence of lung cancer. Preliminary in vivo studies using the non-small cell lung cancer (NCLSC) xenograft model showed that losartan- and astemizole-treated mice had tumors that weighed 50 (p < 0.01) and 15 (p < 0.01) percent less than the treated controls. These results set the stage for further exploration of these drugs and to uncover new drugs for lung cancer therapy.

Original languageEnglish
Pages (from-to)581-591
Number of pages11
JournalMolecular BioSystems
Volume10
Issue number3
DOIs
StatePublished - Mar 2014

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Lung Neoplasms
Pharmaceutical Preparations
Proteins
Therapeutics
Neoplasms
Non-Small Cell Lung Carcinoma
Astemizole
Losartan
Human Genome
Hydrophobic and Hydrophilic Interactions
Heterografts
Medical Records
Phosphotransferases
Molecular Weight
Cell Proliferation
Pharmacology
Ligands

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Biology

Cite this

Exploring a structural protein-drug interactome for new therapeutics in lung cancer. / Peng, Xiaodong; Wang, Fang; Li, Liwei; Bum-Erdene, Khuchtumur; Xu, David; Wang, Bo; Sinn, Anthony A.; Pollok, Karen; Sandusky, George; Li, Lang; Turchi, John; Jalal, Shadia; Meroueh, Samy.

In: Molecular BioSystems, Vol. 10, No. 3, 03.2014, p. 581-591.

Research output: Contribution to journalArticle

Peng, Xiaodong ; Wang, Fang ; Li, Liwei ; Bum-Erdene, Khuchtumur ; Xu, David ; Wang, Bo ; Sinn, Anthony A. ; Pollok, Karen ; Sandusky, George ; Li, Lang ; Turchi, John ; Jalal, Shadia ; Meroueh, Samy. / Exploring a structural protein-drug interactome for new therapeutics in lung cancer. In: Molecular BioSystems. 2014 ; Vol. 10, No. 3. pp. 581-591.
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