Abstract

Traditional lead optimization projects involve long synthesis and testing cycles, favoring extensive structure-activity relationship (SAR) analysis and molecular design steps, in an attempt to limit the number of cycles that a project must run to optimize a development candidate. Microfluidic-based chemistry and biology platforms, with cycle times of minutes rather than weeks, lend themselves to unattended autonomous operation. The bottleneck in the lead optimization process is therefore shifted from synthesis or test to SAR analysis and design. As such, the way is open to an algorithm-directed process, without the need for detailed user data analysis. Here, we present results of two synthesis and screening experiments, undertaken using traditional methodology, to validate a genetic algorithm optimization process for future application to a microfluidic system. The algorithm has several novel features that are important for the intended application. For example, it is robust to missing data and can suggest compounds for retest to ensure reliability of optimization. The algorithm is first validated on a retrospective analysis of an in-house library embedded in a larger virtual array of presumed inactive compounds. In a second, prospective experiment with MMP-12 as the target protein, 140 compounds are submitted for synthesis over 10 cycles of optimization. Comparison is made to the results from the full combinatorial library that was synthesized manually and tested independently. The results show that compounds selected by the algorithm are heavily biased toward the more active regions of the library, while the algorithm is robust to both missing data (compounds where synthesis failed) and inactive compounds. This publication places the full combinatorial library and biological data into the public domain with the intention of advancing research into algorithm-directed lead optimization methods.

Link to full white paper (External website)

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The Stockholm Challenge bring together research communities, development organizations and major corporate programmes, rewarding the initiatives that best accelerate the use of IT for the social and economic benefit of citizens and communities, whilst pro-actively helping local entrepreneurs to close the digital divide.

iShakti is the ICT component of Project Shakti, a micro-enterprise venture providing Indian women’s self-help groups with business skills and income-generating opportunities through the sale of a range of Hindustan Lever products. iShakti information ‘kiosks’ are operated and hosted by Shakti Entrepreneurs. iShakti has grown rapidly over the last year so that it now serves several hundred-thousand users across tens of thousands of rural communities.

Shail Patel, Mathematical & Psychological Sciences Platform Leader at Unilever Corporate Research, said: “iShakti provides information and services to meet a range of rural development needs for the whole community, and also supports Shakti entrepreneurs’ business development. Many organizations act as content partners using iShakti as a communication channel to rural communities.”

Kevin Gell, Managing Director of Tessella, said, “The iShakti project had to overcome a number of unique challenges. Rural telephone connections are often unreliable, preventing routine Internet use. iShakti uses highly efficient and robust synchronization to allow new content to be delivered to an autonomous village-based PC. This enables IT-based information and services to be delivered to regions where this was previously difficult or impossible. This innovative approach is bringing new opportunities to rural India and is positively affecting lives, as well as inspiring other ICT projects in the rural development sector in India.”

Mr Patel continued: “iShakti provides a web-portal with content relevant to the rural audience. Local users can access information on categories including education, employment, agriculture, health, e-governance, personal care, and entertainment. It’s been an enormous privilege working on this project. We are delighted to see that it is positively impacting people’s lives.”

The winners of the Stockholm Challenge awards will be announced in Stockholm on May 11th 2006, in the presence of His Majesty King Carl XVI Gustaf of Sweden.

-ends-

Notes to editors:

For press enquiries or to arrange an interview with Tessella Support Services plc please contact Alison Smith, Marketing Manager on +44 (0) 1235 555511 or e-mail alison.smith@tessella.com

For press enquiries or to arrange an interview with Unilever, please contact Trevor Gorin, trevor.gorin@unilever.com

• 70% of India’s population live in villages and rural areas, where access to information and services can be severely limited. In recent years NGOs and government bodies have been working together to establish self-help groups to stimulate development in these areas, by enabling women to become entrepreneurs and bring much needed income to their families.
• These aims are now receiving a welcome boost from the iShakti project. Under the scheme, each participant village has an iShakti kiosk providing information and advice aimed specifically at rural needs, covering a whole host of subjects such as agriculture, education, vocational training, health and hygiene. This information is provided by content partners including CARE International, and the education-focussed Azim Premji Foundation, who use their experience to ensure that the information provided is relevant to rural users and truly aids the development of the region. Online experts answer kiosk users’ queries, perhaps recommending an appropriate pesticide to a farmer whose crop is in peril, or giving childcare tips to a worried new mother.

To read more about the latest developments in the i-Shakti project, including personal accounts by women who have become i-Shakti entrepreneurs, visit www.hllshakti.com

• Tessella specializes in the application of innovative software solutions to scientific, technical and engineering problems, and has built long-term relationships with organizations at the leading-edge of the scientific and engineering world. Tessella has offices in the UK, the US, and the Netherlands. [www.tessella.com]
• Unilever Corporate Research provides new science for new Unilever business opportunities. With a programme that extends across the academic scientific world, Corporate Research focuses in areas of bioscience and physical and engineering sciences and is based in the UK, India and China.
• Hindustan Lever Limited (HLL) is India’s largest fast-moving consumer goods company, touching the lives of two out of three Indians with over 20 distinct categories in Home & Personal Care Products and Foods & Beverages. [www.hll.com]
• The Stockholm Challenge is a well-established global networking programme for Information and Communication Technology (ICT) entrepreneurs. It continues to be a leader in demonstrating how ICT can improve living conditions and increase economic growth in all parts of the world.

To view the iShakti entry to the Stockholm Challenge Awards online, please visit: www.stockholmchallenge.se/projectdata.asp?id=1&projectid=1007

Tessella contact details:

Tessella Support Services plc
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Abingdon
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Tel: +44 (0) 1235 555511, Fax: +44 (0) 1235 553301

Tessella also has UK offices in Burton upon Trent, Cambridge, Stevenage, Warrington and Winchester.

Unilever contact details:

www.unilever.com

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London
EC4P 4BQ
Tel: +44 (0) 20 7822 5252, Fax: +44 (0) 20 7822 5511

www.hll.com

Hindustan Lever Limited
Hindustan Lever House
165/166, Backbay Reclamation
Mumbai – 400020
Maharashtra, India
Tel: +91-22-22870622, Fax: +91-22-22871970