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Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V.

ABSTRACT: Most orally bioavailable drugs on the market are competitive inhibitors of catalytic sites, but a significant number of targets remain undrugged, because their molecular functions are believed to be inaccessible to drug-like molecules. This observation specifically applies to the development of small-molecule inhibitors of macromolecular interactions such as protein-membrane interactions that have been essentially neglected thus far. Nonetheless, many proteins containing a membrane-targeting domain play a crucial role in health and disease, and the inhibition of such interactions therefore represents a very promising therapeutic strategy. In this study, we demonstrate the use of combined in silico structure-based virtual ligand screening and surface plasmon resonance experiments to identify compounds that specifically disrupt protein-membrane interactions. Computational analysis of several membrane-binding domains revealed they all contain a druggable pocket within their membrane-binding region. We applied our screening protocol to the second discoidin domain of coagulation factor V and screened >300,000 drug-like compounds in silico against two known crystal structure forms. For each C2 domain structure, the top 500 molecules predicted as likely factor V-membrane inhibitors were evaluated in vitro. Seven drug-like hits were identified, indicating that therapeutic targets that bind transiently to the membrane surface can be investigated cost-effectively, and that inhibitors of protein-membrane interactions can be designed.

SUBMITTER: Segers K

PROVIDER: S-EPMC1937529 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V.

Segers Kenneth K Sperandio Olivier O Sack Markus M Fischer Rainer R Miteva Maria A MA Rosing Jan J Nicolaes Gerry A F GA Villoutreix Bruno O BO

Proceedings of the National Academy of Sciences of the United States of America 20070723 31

Most orally bioavailable drugs on the market are competitive inhibitors of catalytic sites, but a significant number of targets remain undrugged, because their molecular functions are believed to be inaccessible to drug-like molecules. This observation specifically applies to the development of small-molecule inhibitors of macromolecular interactions such as protein-membrane interactions that have been essentially neglected thus far. Nonetheless, many proteins containing a membrane-targeting dom ...[more]

PMID: 17646652

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Project description:BACKGROUND:Most electronic health (eHealth) interventions offered to patients serve a single purpose and lack integration with other tools or systems. This is problematic because the majority of patients experience comorbidity and chronic disease, see multiple specialists, and therefore have different needs regarding access to patient data, communication with peers or providers, and self-monitoring of vital signs. A multicomponent digital health cloud service that integrates data sharing, collection, and communication could facilitate patient-centered care in combination with a hospital patient portal and care professionals. OBJECTIVE:This study aimed to assess the feasibility and functionality of a new cloud-based and multicomponent outpatient clinic, the "Virtual Outpatient Clinic" (VOC). METHODS:The VOC consists of 6 digital tools that facilitate self-monitoring (blood pressure, weight, and pain) and communication with peers and providers (chat and videoconferencing) connected to a cloud-based platform and the hospital patient portal to facilitate access to (self-collected) medical data. In this proof-of-concept study, 10 patients from both Departments of Internal Medicine and Dermatology (N=20) used all options of the VOC for 6 weeks. An eNurse offered support to participants during the study. We assessed the feasibility, usage statistics, content, adherence, and identified technical issues. Moreover, we conducted qualitative interviews with all participants by following a standard interview guide to identify user experiences, including barriers, facilitators, and potential effects. RESULTS:Most participants successfully used all options of the VOC and were positive about different tools and apps and the integral availability of their information. The adherence was 37% (7/19) for weight scale, 58% (11/19) for blood pressure monitor, and 70% (14/20) and 85% (17/20) for pain score and daily questions, respectively. The adherence for personal health record was 65% (13/20) and 60% (12/20) for the patient portal system. Qualitative data showed that performance and effort expectancy scored high among participants, indicating that using the VOC is convenient, easy, and time-saving. CONCLUSIONS:The VOC is a promising integrated Web-based technology that combines self-management, data sharing, and communication between patients and professionals. The system can be personalized by connecting various numbers of components, which could make it a relevant tool for other patient groups. Before a system, such as the VOC, can be implemented in daily practice, prospective studies focused on evaluating outcomes, costs, and patient-centeredness are needed.

Dataset Information

Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V.

Publications

Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V.

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