Life Sciences. White Paper. Adopting Future-Forward Discovery Research Strategies: High Performance Computing in the Pharmaceutical Industry

Transcription

1 Life Scieces White Paper Adoptig Future-Forward Discovery Research Strategies: High Performace Computig i the Pharmaceutical Idustry

2 About the Authors Dr Arudhati Saraph Lead High Performace Computig (HPC), Life Scieces At Tata Cosultacy Services (TCS), Arudhati works o leveragig HPC to address scietific problems i iche areas of Life Scieces. These iclude discovery research, geomics, metageomics, predictive toxicology, ad bioiformatics, all of which fid applicatio i the pharmaceutical ad healthcare sectors. Arudhati holds a PhD from the Natioal Chemical Laboratory, Pue, ad has previously worked with several research ad academic istitutios. Aita Suri Domai Cosultat HPC, Life Scieces Aita has expertise i bioiformatics applicatios ad various Life Scieces tools i the HPC eviromet. She has over 10 years of experiece i areas like molecular dockig, molecular dyamics, high throughput virtual screeig, Quatitative Structure Activity Relatioships (QSAR), ad pharmacophore modelig. Aita holds a master's degree i bioiformatics from the Uiversity of Pue. Vivek Sharma Research Aalyst HPC, Life Scieces Vivek has over six years of experiece i usig HPC tools i the Life Scieces domai. He has worked with differet categories of bioiformatics applicatios such as i silico drug discovery, geomics data aalysis, biomolecular simulatio, ad molecular visualizatio. Vivek holds a master's degree i biomedical egieerig from the Idia Istitute of Techology Bombay.

3 Abstract High drug discovery ad developmet costs ad limited patet cycles are kow challeges of the pharmaceutical idustry. A ecoomical drug discovery ad developmet process which successfully leverages research ad developmet (R&D) ca act as a game-chager i this competitive space. Reduced time-to-market plays a key role i drivig performace. It typically takes about 10 years for a potetial ew drug to be registered. Today, the R&D productivity i terms of umbers of ew chemical etities (NCEs) registered per uit amout of ivestmet is decliig due to various factors. Also, there is a high iteratio rate at the cliical trial stage because of the striget Food ad Drug Admiistratio (FDA) regulatios. This is resultig i slower drug approvals, ad reiforcig the eed for icreased R&D productivity. Oe way this ca be doe is by simulatig several steps i the drug discovery process. The simulatios, which geerally leverage HPC, have demostrated reductio i product developmet lifecycles, as well as i product developmet costs ad improved overall productivity. I this paper, we discuss how HPC ca eable pharmaceutical compaies to accelerate biomedical research ad the discovery process.

4 Cotets 1. Itroductio 5 2. Applicatio of HPC i Discovery Research 5 Challeges Ecoutered with HPC platforms 7 HPC eabled Bio-computatio ad simulatio platforms 8 3. Beefits of Leveragig HPC 8 4. Coclusio 9

5 Itroductio The pharmaceutical idustry is at a challegig jucture. Icreasig drug developmet ad marketig costs, shrikig pipelies, expirig patets, demadig regulatory requiremets, chagig healthcare policies, as well as the reducig popularity of the blockbuster drug model call for ew adaptatio strategies. I order to have sufficiet ew molecules i the pipelie, there is a eed to icrease R&D productivity. This ca be achieved by applyig iovative ad cost-effective predictive research methods usig i silico or virtual studies. Simulatios carried out prior to legthy laboratory experimets ad trials ca help aalyze a lot of 'what if' scearios. For istace, the experimetal medicial chemist ad biochemist ca use i silico screes to choose the most promisig drug cadidates ad avoid experimetal dead-eds early i the ew drug discovery cycle. HPC is the practice of aggregatig computig power to deliver much higher performace tha oe could achieve with regular computig ifrastructure. It helps perform complex simulatios at various stages of the ew drug discovery ad developmet process. Applicatio of HPC i Discovery Research Treds i biomedical research show a shift towards traslatioal research which requires better uderstadig of biology. Today, simulatio studies ca be used to explore ew research aveues, throw up ovel isights, ad address problems upfrot o the basis of the simulatio assessmet. These results ca potetially eable a medicial chemist to select the appropriate molecules that ca be take ahead i the pipelie at various stages of the discovery research process. Also, disciplies such as bioiformatics, systems biology, ad ext geeratio sequecig (NGS) are data ad compute-itese applicatios. HPC ca be leveraged to carry out such biosimulatios as well as for bio-computatioal aalysis. Some examples that show how HPC ca be leveraged at differet stages i a product life cycle are give below: Example#1: HPC eables rapid respose to the H1N1 virus A group of scietists from the Uiversity of Illiois, Urbaa- Champaig, carried out i silico studies to assess 1 mutatio or chage i the H1N1 virus that had redered a potet drug Tamiflu ieffective. By appropriately usig the HPC platform, the experimet could be completed i just over a hour. If the simulatios had bee coducted o a CPU this would have take days to complete. The complete study was fairly extesive ad required multiple simulatios to be carried out for a system of 35,000 atoms. The study cocluded that the mutatio that led to the resistace to Tamiflu was due to the disruptio of the bidig fuel, sheddig light o the mechaism behid drug resistace. [1] NVIDIA UK, Uiversity of Illiois: Accelerated Molecular Modellig Eables Rapid Respose to H1N1, 5

6 Example#2 High throughput virtual screeig usig HPC I silico methods such as high throughput virtual screeig (HTVS) ca be used i hit idetificatio. This allows coverig a large chemical space ad reducig the time, effort, ad cost compared to the traditioal high 2 throughput screeig (HTS). Covetioally, HTS allowed a researcher to test millios of compouds i vitro usig robotics. As the umber of molecules that are tested i the chemical space ru ito millios, their acquisitio (or chemical sythesis) ad efficiet testig by sophisticated robots is geerally cost prohibitive ad time cosumig. O the other had, HTVS takes advatage of fast algorithms to filter the chemical space ad successfully select potetial drug cadidates. This reduces the umber of probable hits to be further screeed (i vitro ad i vivo) from the large chemical space of 10⁶⁰ coceivable compouds to a maageable umber that ca be sythesized, 3 purchased, ad tested. A sigificat reductio i time is also achieved by usig computatioal processes. I a study coducted usig a 50,000-core cluster (Amazo Cloud), the computatioal chemistry outfit Schrödiger aalyzed 21 millio drug compouds i just 3 hours for less tha USD 4,900. Usig the traditioal approach, this would have take years to 4 complete ad ivolved a huge sum of moey. The use of a HPC eviromet for HTVS reduces both the time ad cost ivolved i the hit idetificatio stage of the ew drug discovery process. This approach ca also be used at the lead optimizatio stage ad for drug repositioig. Example #3 Use of HPC i NGS ad traslatioal research Techiques like NGS ca help uderstad the geetic origi of diseases, assist i developig more potet regimes for treatig disorders, ad offer alterate strategies to the stadard blockbuster drug approach. The Traslatioal Geomics Research Istitute is leveragig the high throughput gee sequecig techology for precisio therapy trials for childre ad adults with lethal cacers. It uses this iformatio for diagosis ad treatmet tailored to 5 idividuals, for rapidly advacig child cacers. HPC, complex data aalytics platforms, ad high throughput storage systems are some of the key techologies drivig disciplies like NGS ad bioiformatics forward. A robust HPC platform that hosts all the data aalytics tools, various bio-computatioal ad bio-simulatio tools, as well as databases that ca be accessed by multiple users, ca drive research outcomes. Research o biomarker aalysis usig NGS relies o data ad compute-itese activities. To derive meaigful aalysis from the raw results throw up by the sequecig machies or platforms, a umber of computatioal ad data reorgaizatio steps are required. A lot of iformatio stored i databases pertaiig to research data, published work, omics, ad cliical trials ca be used to derive these isights. Such aalysis will aid i better target selectio, research o the developmet of biomarkers for diagostics, ad i the log ru reduce phase II ad III attritio. Studies o bidig betwee potetial drugs ad proteis i the body ca help idetify cross biders that ca be elimiated ahead of legthy ad expesive experimetal stages of developmet. Figure 1 depicts how iformatio from various sources ca be used to coduct bio-simulatios ad computatios upfrot before coductig legthy experimetal procedures to test several 'what if' scearios. [2] Supercomputig facility for Bioiformatics ad Computatioal Biology, IIT Delhi, Virtual high throughput screeig: will it help for lead idetificatio?, accessed o 10 February 2015, [3] Iteratioal Joural of Advaced Research i Computer Sciece ad Software Egieerig, Isilico Methods i Drug Discovery-A Review, May 2013, accessed i 11 February 2015, {4} Giagaom,Cycle Computig spis up 50K core Amazo cluster, April 2012, accessed o 4 February [5] DataDirect Networks, Geomics Research (DDN case study) 2011, accessed o 28 Jauary

7 Pharmacogeomics approach likig biomarkers to therapeutics Successful outcome i select populatio Target to hit Hit to lead Lead optimizatio Precliical Precliic al Phase 1 Phase II Phase III Submissio to lauch Lauch Bio-simulatio platforms Bio-iformatics platform Geomics platform Model based drug developmet Novel target idetificatio Iformatio repository Research Published Cliical NGS Figure 1: Use of the I silico Approach at Various Stages i the Product Life Cycle of a New Chemical Etity Challeges ecoutered with HPC platforms Computatioal aalysis i each area of discovery research requires a differet set of tools, each with a specific compute, iput output (I/O), ad throughput requiremet. For istace, the amout of compute, I/O, ad memory requiremet for optimal performace o a bio-simulatio ru could be differet from resource requiremet for geomics tools carryig out sequece aligmet. Suboptimal use of resources such as memory or I/O ca eve lead to poor performace or applicatio failures. Furthermore, to carry out accurate ad speedy aalysis of the cliical data, the data has to be accessed, processed, aalyzed, ad visualized. Ofte, this requires movemet of data from the storage device to cluster odes for further aalysis, which becomes challegig as the data size icreases. This research data geerated through microarray ad cell aalyzer systems is image based ad geerally requires both short ad log term storage. Also, the data ad results geerated at the discovery research step as well as various steps i the ew drug discovery cycle have to be studied ad aalyzed by various groups workig across the orgaizatio. This icreased movemet of data back ad forth betwee differet types of temporary storage ca create bottleecks ad lead to suboptimal performace. Storage thus becomes a critical resource requiremet for all data-drive research, especially i NGS aalysis, as there is a huge eed for data access ad data storage both short term ad for data archival purposes. Cosiderig these challeges, it is difficult to provide optimal HPC architecture i scearios with the followig diverse requiremets: Algorithmic complexity ad high compute-itesive platform requiremets Distributed computig solutios eedig low latecy etwork-cetric HPC 7

8 High throughput file systems which ca access ad sychroize data at multiple gigabytes Architectures providig large-scale memory Large data aalysis ad iformatio extractio requirig data miig Acquirig iformatio i multiple data formats from a variety of sources requirig low latecy ad high throughput systems Graphics ad visualizatio demads askig for ear real time solutios Complete kowledge ad uderstadig of the resource requiremet for each class of applicatios used i the idustry is required to address the above eeds. HPC eabled platforms that host workflows to carry out various aalyses i areas of geomics, bio-simulatios, or bioiformatics eable scietists to focus o aalyzig results ad address domai related problems without spedig time o resolvig software or ifrastructure-related issues. HPC eabled Bio-computatio ad simulatio platforms A bio-computatio ad simulatio service through the use of workflows or pipelies ca be used as a prepackaged solutio to address problems i discovery research. The mai focus would be to see how computatios go a log way i supportig the traditioal R&D activity. Recet advaces i software techiques have made it possible to combie software tools ad iformatio bases, makig it possible to offer predefied software solutios to domai problems. The scietific workflow system is a specialized form of a workflow maagemet system desiged specifically to compose ad execute a series of computatioal or data maipulatio steps. Essetial requiremets of a HPC-eabled work-flow or pipelie are as follows: 1. Strog domai kowledge, both breadth ad depth 2. A set of software techologies that ca create a user friedly ad expressive iterface 3. A assortmet of well-trusted software tools 4. A software suite that allows the combiatio of the tools ad takes care of the itegratio 5. A cluster maagemet suite that maages the computer hardware usually a etwork of clusters A robust HPC ifrastructure should cater to variable work load requiremets. It should use optimal resources through cluster ad data maagemet tools ad job schedulig software to efficietly ru the simulatios. Beefits of Leveragig HPC By applyig the HPC approach pharmaceutical eterprises ca: Accelerate drug discovery: HPC ca be used to accelerate several steps like target idetificatio ad validatio, hit idetificatio, cross bidig studies, ad drug repositioig i the ew drug discovery process. 8

9 Explore ew research aveues: HPC techology ca successfully execute large simulatios which otherwise take loger to complete or are abadoed due to computig resource shortfalls, thus eablig ew research opportuities. Ehace orgaizatioal focus: HPC eabled platforms that host work-flows to carry out various aalyses i the areas of geomics, ru bio-simulatios, or coduct bioiformatics aalysis allow scietists to focus o aalyzig results ad address domai-related problems without spedig time o resolvig software ad IT related issues Execute tasks faster: Use of HPC eabled workflows ad platforms simplify solutio usage ad execute tasks faster by reducig the simulatio rutime Coclusio Complex, compute-itese applicatio areas i the early stages of drug discovery such as target idetificatio ad validatio, hit or lead idetificatio, cross bidig studies, ad NGS aalysis ca beefit from the use of HPC. With the costat growth i data volumes ad the requiremet to carry out multiple aalyses there arises a eed to move large volumes of data from storage device to cluster odes. To achieve this, there is a eed for high performace as well as scalable I/O, as performace bottleecks at ay of these steps result i delays i the dowstream aalysis. To avoid this, there should be a efficiet access of data across servers as well as hassle-free data movemet betwee differet tiers of storage to support variable work load. This ca be realized with the use of a HPC system that eables optimal utilizatio of the ifrastructure through cluster ad data maagemet tools providig optimal performace ehacemet. HPC eabled platforms or work-flows are istrumetal i addressig problems through virtual or i silico studies at various steps i the discovery research. Use of HPC eabled platforms i other areas i dowstream drug discovery icludig cliical trial aalysis, supply chai maagemet, drug safety aalysis, ad health ecoomics ca also be beeficial. A HPC platform that hosts ed-to-ed applicatios ad coducts seamless itegratio of workflows likig the discovery, developmet, ad cliical trial aalysis to the dowstream supply chai ca eable a pharmaceutical compay to efficietly carry out ew drug discovery ad ultimately reduce the time-to-market. 9

10 About TCS Life Scieces With over two decades of experiece i the life scieces domai, TCS offers a comprehesive portfolio i IT, Cosultig, KPO, Ifrastructure ad Egieerig services as well as ew-age busiess solutios icludig mobility ad big data caterig to compaies i the pharma, biotech, medical devices, ad diagostics idustries. Our offerigs help cliets accelerate drug discovery, advace cliical trial efficiecies, maximize maufacturig productivity, ad improve sales ad marketig effectiveess. We draw o our experiece of havig worked with 7 of the top 10 global pharmaceutical compaies ad 8 of the top 10 medical device maufacturers. Our commitmet towards developig ext geeratio iovative solutios ad facilitatig cuttig-edge research - through our Life Scieces Iovatio Lab, research collaboratios, multiple ceters of excellece ad Co-Iovatio Network TM (COIN ) - have made us a preferred parter for the world's leadig life scieces compaies. Cotact For more iformatio, cotact lshcip.pmo@tcs.com Subscribe to TCS White Papers TCS.com RSS: Feedburer: About Tata Cosultacy Services (TCS) Tata Cosultacy Services is a IT services, cosultig ad busiess solutios orgaizatio that delivers real results to global busiess, esurig a level of certaity o other firm ca match. TCS offers a cosultig-led, itegrated portfolio of IT ad IT-eabled ifrastructure, egieerig ad TM assurace services. This is delivered through its uique Global Network Delivery Model, recogized as the bechmark of excellece i software developmet. A part of the Tata Group, Idia s largest idustrial coglomerate, TCS has a global footprit ad is listed o the Natioal Stock Exchage ad Bombay Stock Exchage i Idia. For more iformatio, visit us at IT Services Busiess Solutios Cosultig All cotet / iformatio preset here is the exclusive property of Tata Cosultacy Services Limited (TCS). The cotet / iformatio cotaied here is correct at the time of publishig. No material from here may be copied, modified, reproduced, republished, uploaded, trasmitted, posted or distributed i ay form without prior writte permissio from TCS. Uauthorized use of the cotet / iformatio appearig here may violate copyright, trademark ad other applicable laws, ad could result i crimial or civil pealties. Copyright 2015 Tata Cosultacy Services Limited TCS Desig Services I M I 03 I 15