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Polypharmacology Analysis of Anti-osteoporosis Agents and Cannabinoid 2 Receptor Inverse Agonists for Osteoporosis Drug Research

Fang, Cheng (2014) Polypharmacology Analysis of Anti-osteoporosis Agents and Cannabinoid 2 Receptor Inverse Agonists for Osteoporosis Drug Research. Master's Thesis, University of Pittsburgh. (Unpublished)

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Osteoporosis (OP) is a complex bone metabolic disease indicated by excess bone resorption over bone formation. Some cannabinoid receptor 2 (CB2) inverse agonists have shown dual antiresoptive and anabolic effects, and thus are potential anti-OP agents. However, the underlying mechanism, especially for their anabolic effects, is not very clear. To fully understand the pharmaceutical roles of CB2 inverse agonists, we implement polypharmacology analysis by using two off-target prediction tools (HTDocking and TargetHunter). First, we construct osteoporosis domain specific knowledgebase (OP-KB) that contains the data of anti-OP targets, related proteins, drugs, and chemicals collected from a variety of available databases. Five approved anti-OP drugs undergo HTDocking to screen all OP-related proteins in OP-KB for the detection of potential off-targets. This prediction validates the reliability of HTDocking method in OP-KB based on the concordance of actual and predicted targets. Similarly, we analyze polypharmacological effects of six CB2 inverse agonists including two in-house compounds (Xie95-1042, Xie95-1171). Potential targets are predicted and ranked based on the degree of connectivity to drugs. To validate our prediction and reveal possible interaction modes, we perform molecular docking between two in-house compounds and AM630 with six top predicted targets that are all responsible for bone formation. We observe similar binding interactions between these three compounds with similar nearby residues in comparison to initial crystal structures. Hence, we hypothesize that CB2 inverse agonists may act on other anti-osteoporosis targets such as NOS3, DHI1, VDR, ALDH2, TRFL and ESR1 to achieve their anabolic effect for bone formation. In addition, TargetHunter is used to predict off-targets beyond OP-related protein list. Based on the prediction of two in-house compounds, aldehyde dehydrogenase 1A1 (ALDH1A1), a key protein involved in cancer development discovered recently, is probably another target for those two CB2 inverse agonists. This finding may imply new mechanism of the anti-cancer effect of CB2 inverse agonists, and also facilitate relevant drug repurposing. In summary, our approach provide a paradigm for polypharmacology study on a specific disease domain, which we believe can be widely applied to other complex diseases study to accelerate drug discovery.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Fang, Chengchf42@pitt.eduCHF42
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXie, Xiang-Qunxix15@pitt.eduXIX15
Committee MemberFolan, Maggiefolanm@pitt.eduFOLANM
Committee MemberWang, Lirongliw30@pitt.eduLIW30
Thesis AdvisorXie, Xiang-Qunxix15@pitt.eduXIX15
Date: 16 April 2014
Date Type: Publication
Defense Date: 31 March 2014
Approval Date: 16 April 2014
Submission Date: 11 April 2014
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 77
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Polypharmacology analysis; Cannabinoid 2 receptor inverse agonist; Osteoporosis;Osteoporosis domain specific knowledgebase(OP-KB; HTDocking; TargetHunter;
Date Deposited: 16 Apr 2014 19:24
Last Modified: 16 Apr 2019 05:15


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