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J Comput Aided Mol Des (2014) 28:347362 DOI 10.1007/s10822-014-9721-7
Interrogating HIV integrase for compounds that bind- a SAMPL challenge
Thomas S. Peat Olan Dolezal Janet Newman
David Mobley John J. Deadman
Received: 14 November 2013 / Accepted: 25 January 2014 / Published online: 16 February 2014 Springer International Publishing Switzerland 2014
Abstract Tremendous gains and novel methods are often developed when people are challenged to do something new or difcult. This process is enhanced when people compete against each other-this can be seen in sport as well as in science and technology (e.g. the space race). The SAMPL challenges, like the CASP challenges, aim to challenge modellers and software developers to develop new ways of looking at molecular interactions so the community as a whole can progress in the accurate predictionof these interactions.In order for this challenge to occur, data must be supplied so the prospective test can be done. We have supplied unpublished data related to a drug discovery program run several years ago on HIV integrase for the SAMPL4 challenge. This paper describes the methods used to obtain these data and the chemistry involved.
Keywords HIV integrase Structure based drug design
SPR Crystallography SAMPL challenge
Introduction
The AIDS epidemic has caused over 32 million deaths and over 33 million people are currently infected with HIV
(WHO data, http://UNAIDS.org
Web End =http://UNAIDS.org ). Small molecule therapeutics against several different protein targets of the HIV virus have been developed over the past two decades [14] culminating in a drug combination regimen referred to as Highly Active AntiRetroviral Therapies (HAART) used to treat AIDS. However, these therapies only slow the replication of the virus in patients and new forms of the virus have appeared that are resistant to all the drugs to date [5, 6], so there is a continuing need for new drugs. The integrase enzyme (IN) is critical to the viral life cycle as it is required for the integration of viral DNA into the host chromatin, which in turn is required for formation of new copies of the virus. Integrase performs two catalytic functions termed 3 processing-cleaving two nucleotides off of the viral cDNA in a sequence-specic manner to generate sticky ends and the strand transfer reaction-which covalently attaches, or integrates, the cleaved...