Drug Search for Leishmaniasis, поиск лекарств от Лейшманиоза Налаштування

[Rilian]

Thanks for all people supporting the DSFL project

Dear WCG members.

This is a short message just to thanks all members (crunchers) of the WCG supporting the project Drug Search for Leishmaniasis (DSFL) for the almost 19 millions results processed and returned to the World community grid out of the 1 billion results results. Hope we can continue receiving this help to try to get a new safe and cheap drug for the leishmaniasis treatment.

Best wishes from Colombia and thanks again

[Death]

19 millions results processed and returned to the World community grid out of the 1 billion results results

то есть 1.9% посчитали?

[Rilian]

19 millions results processed and returned to the World community grid out of the 1 billion results results

то есть 1.9% посчитали?

нет, просто недавно ВЦГ преодолели рубеж в 1 МЛРД посчитанных заданий, из них 1.9% это ДСФЛ

[Rilian]

Апдейт проекта

Drug Search for Leishmaniasis Update

Rodrigo Ochoa and Carlos Muskus

The project “Drug Search for Leishmaniasis” has been running during 10 months, and the following is a brief description of our progress and what have been validated until now:

The original project included the evaluation of 53 crystallized Leishmania proteins obtained from the PDB database along with 5,300 modelled structures, (100 modelled structures for each protein downloaded from PDB) (figure 1). The modelling was carried out through Molecular Dynamics using the NAMD program, representing an indirect way to provide flexibility for each one of the potential targets.

However, based on the statistic of the project after 6 months of activity, to run the 5.353 protein structures against the 600.000 compounds will spend around 20-25 years to complete. These made us to reconsider the project just prioritizing 10 structures for each of the 53 proteins for a total of 530 structures (Phase 2). Originally the idea was to build a molecular trajectory using snapshots of a protein during a computational simulation, trying to mimic the biological environment of the protein inside the organism. The trajectories contain 100 snapshots. Nevertheless, to prioritize the data, 10 snapshots per trajectory (i.e from the 100 structures per protein, the snapshots 10, 20, 30, 40, 50, 60, 70, 80 90 and 100 were selected) (see figure 2). That rational selection pretends to cover substantial changes in the conformation of the binding site of the protein.

Currently, WCG have processed approx. 76.200.000 docking simulations (127 structures against 600.000 compounds in phase I). From the second phase, it has processed approx. 37.800.000 docking simulations (63 priority structures against the same 600.000 compounds). Due to the huge amount of data, only the top 20 compounds per structure (compounds with the best score hits) and based on the score function proposed by the AutoDock VINA software, have been extracted. As an example, we provided the top 20 compound which lists from the protein 1-10, 1-20 and 1-30* (See tables 1, 2 and 3)
*The notation 1-10 means the modelled structure 10, from the protein target 1 of the 53 original proteins downloaded from PDB database.
A future analysis with the high relevant results will be published in the next update of the project.

Figure 1. Representation of the 53 original PDB proteins (black-red squares at the bottom), and the 5300 (blue squares) modelled proteins. Solid Red squares along with the black-red squares represent 127 proteins that were already docked against the 600.000 compounds in the first phase of the project

Figure 2. Priority targets (530 structures) are represented by solid red squares and are being docked against the 600.000 compounds. Modelled protein 1 is more similar in structure to the original proteins obtained from PDB than modeled protein structure 100. Sixty three priority structures out of the 530 have been already docked against the 600.000 compounds.

Table 1. Top 20 docking results for modelled structure 10 from the protein target number 1.


Table 2. Top 20 docking results for modelled structure 20 from the protein target number 1.


Table 3. Top 20 docking results for modelled structure 30 from the protein target number 1.

[Bel]

Среднее время выполнения всех заданий увеличилось на 20%!

[Rilian]

Current status of the Drug Search for Leishmaniasis project

When we initially launched the project in September 2011 on World Community Grid, we planned on using Autodock-Vina to evaluate the docking of 5,353 protein structures from the Leishmania parasite against 600,000 chemical compounds selected and filtered from the ZINC database. The software measures the protein-compound interaction in a three dimensional space and generates a score according to the degree of affinity. The 5,353 protein structures correspond to 53 Leishmania proteins for which the crystal structures were obtained from x-ray crystallography information found in the Protein Data Bank (PDB) along with 100 alternate modeled protein structures for each of the 53 original structures. However, the rate of progress showed that it would take 20-25 years to compute all of these interactions. Therefore we prioritized the 5,353 structures and focused on just 530 modeled structures along with the 53 original PDB structures for a total of 583 structures. This would give us useful results much sooner.

The table loaded in the news section at PECET website summarizes the status of the DSFL project. Each of the cells on the table corresponds to any of the 5,353 structures, both original and modeled. The green cells correspond to the 53 original structures from PDB (bottom horizontal row) and 75 modeled structures of the first PDB protein (first column) already docked before prioritizing the 530 structures. The blue cells correspond to the 530 modeled and prioritized structures that have been already docked against the 600,000 compounds. And finally, the red cells correspond to those 530 priority structures pending to be processed.

We give a very big “thank you” to the World Community Grid members for contributing to this project!

Кратко: всего надо ісследовать взаімодействіе 5353 белков, із ніх 530 рассчітиваются с большім пріорітетом так как оні важнее. В таблічке видно существующий прогресс

http://www.worldcommunitygrid.org/forums/w...ad_thread,34157

[Sonechko]

Sapphire - done

[Rilian]

Апдейт проекта

посчитано 67%

Drug Search for Leishmaniasis Update

Rodrigo Ochoa and Carlos Muskus





The project “Drug Search for Leishmaniasis” has been running during 10 months, and the following is a brief description of our progress and what have been validated until now:

The original project included the evaluation of 53 crystallized Leishmania proteins obtained from the PDB database along with 5,300 modelled structures, (100 modelled structures for each protein downloaded from PDB) (figure 1). The modelling was carried out through Molecular Dynamics using the NAMD program, representing an indirect way to provide flexibility for each one of the potential targets.

However, based on the statistic of the project after 6 months of activity, to run the 5.353 protein structures against the 600.000 compounds will spend around 20-25 years to complete. These made us to reconsider the project just prioritizing 10 structures for each of the 53 proteins for a total of 530 structures (Phase 2). Originally the idea was to build a molecular trajectory using snapshots of a protein during a computational simulation, trying to mimic the biological environment of the protein inside the organism. The trajectories contain 100 snapshots. Nevertheless, to prioritize the data, 10 snapshots per trajectory (i.e from the 100 structures per protein, the snapshots 10, 20, 30, 40, 50, 60, 70, 80 90 and 100 were selected) (see figure 2). That rational selection pretends to cover substantial changes in the conformation of the binding site of the protein.

Currently, WCG have processed approx. 76.200.000 docking simulations (127 structures against 600.000 compounds in phase I). From the second phase, it has processed approx. 37.800.000 docking simulations (63 priority structures against the same 600.000 compounds). Due to the huge amount of data, only the top 20 compounds per structure (compounds with the best score hits) and based on the score function proposed by the AutoDock VINA software, have been extracted. As an example, we provided the top 20 compound which lists from the protein 1-10, 1-20 and 1-30* (See tables 1, 2 and 3)

*The notation 1-10 means the modelled structure 10, from the protein target 1 of the 53 original proteins downloaded from PDB database.

A future analysis with the high relevant results will be published in the next update of the project.



Figure 1. This new graph represent the current progress of the 583 priority targets (530 modelled proteins + 53 original structures) docked against the 600.000 compounds. The red bar at the botton of the figure represents the 53 original proteins structures already docked. The others bars represent the modelled protein structures (from 10 to 100). The blue color areas represent modelled proteins already docked and the green color areas represent the modelled proteins pendindg for docking. As you can see there are 203 modelled structures pending for docking which correspond to approximately 35%.

[Rilian]

DSFL update - April 11, 2013

Dear DSFL Collaborators

With your help or contribution, 71% of the priority proteins have been processed against the 600.000 compounds. According to the statistic of the project, it is estimated to end in the middle of august this year.

An update of the project have been loaded in the project website:

Thank to all of you for your collaborations.

The project “Drug Search for Leishmaniasis” has been running during 10 months, and the following is a brief description of our progress and what have been validated until now:

The original project included the evaluation of 53 crystallized Leishmania proteins obtained from the PDB database along with 5,300 modelled structures, (100 modelled structures for each protein downloaded from PDB) (figure 1). The modelling was carried out through Molecular Dynamics using the NAMD program, representing an indirect way to provide flexibility for each one of the potential targets.

However, based on the statistic of the project after 6 months of activity, to run the 5.353 protein structures against the 600.000 compounds will spend around 20-25 years to complete. These made us to reconsider the project just prioritizing 10 structures for each of the 53 proteins for a total of 530 structures (Phase 2). Originally the idea was to build a molecular trajectory using snapshots of a protein during a computational simulation, trying to mimic the biological environment of the protein inside the organism. The trajectories contain 100 snapshots. Nevertheless, to prioritize the data, 10 snapshots per trajectory (i.e from the 100 structures per protein, the snapshots 10, 20, 30, 40, 50, 60, 70, 80 90 and 100 were selected) (see figure 2). That rational selection pretends to cover substantial changes in the conformation of the binding site of the protein.

Currently, WCG have processed approx. 76.200.000 docking simulations (127 structures against 600.000 compounds in phase I). From the second phase, it has processed approx. 37.800.000 docking simulations (63 priority structures against the same 600.000 compounds). Due to the huge amount of data, only the top 20 compounds per structure (compounds with the best score hits) and based on the score function proposed by the AutoDock VINA software, have been extracted. As an example, we provided the top 20 compound which lists from the protein 1-10, 1-20 and 1-30* (See tables 1, 2 and 3)

*The notation 1-10 means the modelled structure 10, from the protein target 1 of the 53 original proteins downloaded from PDB database.

A future analysis with the high relevant results will be published in the next update of the project.


Figure 1. This new graph represent the current progress of the 583 priority targets (530 modelled proteins + 53 original structures) docked against the 600.000 compounds. The orange bar at the bottom of the figure represents the 53 original proteins structures already docked. The others bars represent the modelled protein structures (from 10 to 100). The blue color areas represent modelled proteins already docked and the green color areas represent the modeled proteins pending for docking. As you can see, there are 136 modelled structures still pending for docking which correspond to approximately 29%.

We want also to thank all the WCG members supporting this project all over the world, for the almost 19.000.000 results processed, out of the 1 billion data returned to the World Community Grid from IBM.

[Rilian]

Сообщение описывает с медицинской точки зрения, почему проект ищет новые варианты противодействия, несмотря на то что цены на существующие аналоги падают.

Comments on amphotericn B and why seacrhing new drugs
Dear DSFL cruncher

Amphotericin B is a drug that have been used as a second choice for the Leishmaniasis treatment in many endemic areas and with good efficay. Initially, it was administered parenterally in those patients that did not respond to the antimonials. However, it could caused severe side effects and other times it was contraindicated for certain patients. Then it was encapsulated in liposomes (a lipid bag) and the severe side effect diminished, but it was expensive. Currently, the company manufacturing this presentation cut the price and it uses as antileishmania agent have been extended. However, in spite of it decrease in toxicity and price, in this liposome presentation, the administration have to be parenteral.
It is good to know that promising studies to administer amphotericin B orally are in course at least for Visceral Leishmaniasis, which is mainly caused by two Leishmania species (Leishamnia donovani and Leishmania infantum).

We have been testing an ointment presentation of amphotericin B, with also promising results, obviously for cutaneous leishmaniasis which are approximately 1.5 million cases per year.

But why to continue searching for new drugs??. Among several reason are:
1. The number of alternative options are few. We need more or alternative options
2. The efficacy of the current drugs (included amphotericin B) can be variable depend on the Leishmania species (there are more than 20 Leishmania species associated with disease in human).
3. Development of parasite resistance when administration of amphotericin B is authorized in most endemic countries as first option, is a probability. We have to be prepared to face it.
4. The administration of amphotericin B may be contraindicated in some patients with particular condition.
5. And why to administer a systemic drug with some toxicity for treating a cutaneous ulcer?.
6. Cost may be also a reason given Leishmaniasis is mostly endemic in poor countries or affecting poor communities.
There are even more reason.

Best wishes
carmusk
Drug Search for Leishmaniasis Scientists

[Rilian]

07 Jun 2013

Drug Search for Leishmaniasis project update

Summary
A poster, containing preliminary Drug Search for Leishmaniasis project results, presented at the WorldLeish5 Congress in Porto de Galinhas-Brasil in May 2013.


The following Drug Search for Leishmaniasis project update can be found here .

Dear DSFL cruncher.
I am loading a poster with preliminary results from the DSFL project. This poster was presented in the past WorldLeish5 Congress in Porto de Galinhas-Brasil from May 13 to 17. Given this is the World Congress on Leishmaniasi and attended by the most important scientific working on Leishmaniasis from all over the world, I could see that none lab is doing an ambicious work like this in terms of searching new drugs for Leishmaniasis, and this has been possible for all your support as was mentioned in the acknowledge section of if. Some researchers attending the meeting and working in drug discovery were talking with me about the project and were a bit impressed. Thanks again and we are almost close to finish the project.

After we finish the computational work, we ill start the second part, which consist of filtering and selecting the potential candidates to test them in vitro and in vivo. The selection steps is based in the Autodock vina score, if the potential compound has human approval use, oral administration, cost, etc.

Best wishes and thanks

[Rilian]

Осталось менее 100 дней до завершения проекта!

Спешите заработать бейджик!

[Rilian]

по моим подсчетам 1 фаза проекта закончится где-то через 60 дней

[MAGADAN]

Что у них резкий скачет пошол вниз по дням
И на этом проекте я могу пролететь с Сапфиром
Rilian если у меня щас 193 дня , и средняя 6 дней производительность я успею добраться до САПФИРА при условии что не будет разких скачков вниз по дням ?

[Rilian]

MAGADAN, скачки резкие будут так как в ВЦГ щяс только 2 проекта работают в полную мощность. Этот и FAAH. То есть все 400 процессорных лет в день направлены сюда.

так что я бы рекомендовал все силы сюда направить если ты планируешь добраться до бейджика