- Feb 15, 2001
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The following is a cut and paste from the TSC forums on how TSC and d2ol works:
Dear community members,
We have always said that we are doing good science and that all the results we obtain will be used to develop new drugs against childhood diseases. With a few postings that will be released over the next week I will attempt to explain to the community how they are helping to develop drugs against TSC. This particular posting will be reposted in the technical forum so that users can pose questions about the topic under discussion. References will be listed at the end of this discussion.
The Science behind D2OL ? An introduction:
1. Modern Principles of Drug Design
Before the advance of modern biology, chemistry, and computer science, drug development was based on trial and error experiments in which the healing effects of medicinal substances (often a complex mixture of compounds such as herbal extracts) were tested on patients displaying a certain set of symptoms. The advance of modern medicine and biology has enabled scientist to determine specific causes of many diseases and disorders. This understanding is crucial for the directed design and development of compounds that reverse the symptoms and/or heal the patient completely whilst showing few or negligible side effect. Early in the 20th century, many drugs were discovered serendipitously. The goal over the past 30 years has been to make use of newly gained insight into the cause of diseases/disorders and design the most effective and specific drugs possible.
?Computer aided drug design? is the term used to describe the rational design of drugs based on specific knowledge available for a certain diseases or disorder. Several basic assumptions are made in this process:
I ) The symptoms of a diseases/disorder can be attributed to the dysfunction of one or several specific protein(s) (or other large biomolecule). These proteins represent a target for small molecule (drug) interaction which enhance or disrupt their normal function. Cellular proteins can function in several ways. They can exhibit enzymatic activity, mediate protein-protein or protein-nucleic acid interactions, and/or localize other proteins within the cell.
II) By enhancing or disrupting the native function of the protein, symptoms of the disease/disorder are alleviated and/or cured.
III) In the case of infectious diseases, one would like to disrupt the function of the viral /microbial protein target such that the pathogen is unable to survive or replicate (e.g. antibiotics, antiviral and antifungal agents). This interaction must be pathogen-specific so that the human host is unaffected by the same small molecule. Often bacteria and viruses have proteins which are specific to their systems and are required for the survival and/or replication of the pathogen. These proteins are ideal drug targets.
The Lock and Key Principle:
We now know that the interaction of a small molecule and protein target forms the basis for modern rational drug design. The question remains: what type of interaction are we looking for? Often it is necessary for the small molecule to bind the protein at a specific site in order to obtain the desired effect. Thus the protein can be compared to a lock which requires a specific key (the small molecule in our case) to alter its deleterious function.
For any key to work, it has to have just the right shape and be inserted properly. Analogously, the small molecule must be the right shape and bind in just the right fashion. This lock-and-key hypothesis has been repeatedly supported by X-ray crystal structures of drugs bound to concave pockets on the protein surface.
The binding of small molecules to proteins can be measured by various techniques in biochemical assays and screens. These assays are very expensive since they require large amounts of purified protein (a challenge in itself) and reasonable quantities of the drug to be tested. Extensive research in the field of virtual library screening over the past 10 years has culminated in the development of software that can predict how well any given molecule can bind to a site on the protein surface (binding constant). The methods used have improved over the years and have become more accurate in predicting which molecules would be good drug leads to test in the aforementioned biochemical assays. Since the computational methods make several assumptions they are close approximations to the real binding constants forcing us to screen not only the top 5 compounds but more likely the top 5 % of the compounds as ranked by the software.
This concludes the introduction. The following topics will be covered in the next several days:
2) Automated Docking ? Using genetics algorithms in the search for the perfect key!
3) Result Analysis ? What do we hope to achieve? How do we know we are doing the right thing?
4) Libraries ? The selection criteria, why do we use the compounds that we use?
5) Target Selection - What are the targets relevant to TSC?
Please feel free to comment and ask questions in the forum below this posting.
--------------------
Wolfgang Hinz
Senior Research Scientist - Chemistry/Informatics
The Rothberg Institute
Guilford, CT
www.childhooddiseases.org
--------------------------------------------------------------------------------
Dear community members,
We have always said that we are doing good science and that all the results we obtain will be used to develop new drugs against childhood diseases. With a few postings that will be released over the next week I will attempt to explain to the community how they are helping to develop drugs against TSC. This particular posting will be reposted in the technical forum so that users can pose questions about the topic under discussion. References will be listed at the end of this discussion.
The Science behind D2OL ? An introduction:
1. Modern Principles of Drug Design
Before the advance of modern biology, chemistry, and computer science, drug development was based on trial and error experiments in which the healing effects of medicinal substances (often a complex mixture of compounds such as herbal extracts) were tested on patients displaying a certain set of symptoms. The advance of modern medicine and biology has enabled scientist to determine specific causes of many diseases and disorders. This understanding is crucial for the directed design and development of compounds that reverse the symptoms and/or heal the patient completely whilst showing few or negligible side effect. Early in the 20th century, many drugs were discovered serendipitously. The goal over the past 30 years has been to make use of newly gained insight into the cause of diseases/disorders and design the most effective and specific drugs possible.
?Computer aided drug design? is the term used to describe the rational design of drugs based on specific knowledge available for a certain diseases or disorder. Several basic assumptions are made in this process:
I ) The symptoms of a diseases/disorder can be attributed to the dysfunction of one or several specific protein(s) (or other large biomolecule). These proteins represent a target for small molecule (drug) interaction which enhance or disrupt their normal function. Cellular proteins can function in several ways. They can exhibit enzymatic activity, mediate protein-protein or protein-nucleic acid interactions, and/or localize other proteins within the cell.
II) By enhancing or disrupting the native function of the protein, symptoms of the disease/disorder are alleviated and/or cured.
III) In the case of infectious diseases, one would like to disrupt the function of the viral /microbial protein target such that the pathogen is unable to survive or replicate (e.g. antibiotics, antiviral and antifungal agents). This interaction must be pathogen-specific so that the human host is unaffected by the same small molecule. Often bacteria and viruses have proteins which are specific to their systems and are required for the survival and/or replication of the pathogen. These proteins are ideal drug targets.
The Lock and Key Principle:
We now know that the interaction of a small molecule and protein target forms the basis for modern rational drug design. The question remains: what type of interaction are we looking for? Often it is necessary for the small molecule to bind the protein at a specific site in order to obtain the desired effect. Thus the protein can be compared to a lock which requires a specific key (the small molecule in our case) to alter its deleterious function.
For any key to work, it has to have just the right shape and be inserted properly. Analogously, the small molecule must be the right shape and bind in just the right fashion. This lock-and-key hypothesis has been repeatedly supported by X-ray crystal structures of drugs bound to concave pockets on the protein surface.
The binding of small molecules to proteins can be measured by various techniques in biochemical assays and screens. These assays are very expensive since they require large amounts of purified protein (a challenge in itself) and reasonable quantities of the drug to be tested. Extensive research in the field of virtual library screening over the past 10 years has culminated in the development of software that can predict how well any given molecule can bind to a site on the protein surface (binding constant). The methods used have improved over the years and have become more accurate in predicting which molecules would be good drug leads to test in the aforementioned biochemical assays. Since the computational methods make several assumptions they are close approximations to the real binding constants forcing us to screen not only the top 5 compounds but more likely the top 5 % of the compounds as ranked by the software.
This concludes the introduction. The following topics will be covered in the next several days:
2) Automated Docking ? Using genetics algorithms in the search for the perfect key!
3) Result Analysis ? What do we hope to achieve? How do we know we are doing the right thing?
4) Libraries ? The selection criteria, why do we use the compounds that we use?
5) Target Selection - What are the targets relevant to TSC?
Please feel free to comment and ask questions in the forum below this posting.
--------------------
Wolfgang Hinz
Senior Research Scientist - Chemistry/Informatics
The Rothberg Institute
Guilford, CT
www.childhooddiseases.org
--------------------------------------------------------------------------------
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