computer-aided discovery of new hiv-1 integrase inhibitors (istc/btep project # 3197/111) vladimir...
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Computer-Aided Discovery of New
HIV-1 Integrase Inhibitors
(ISTC/BTEP Project # 3197/111)
Vladimir Poroikov
Laboratory for Structure-Function Based Drug Design, Institute of Biomedical Chemistry of Rus. Acad. Med. Sci.
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Slovenja: The Land of Many Dreams
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Acquired immunodeficiency syndrome (AIDS), which is
caused by HIV, is an immunosuppressive disease that
results in life-threatening opportunistic infections and
malignancies. First reported in 1981 in the United States,
AIDS has become a major worldwide epidemic. The United
Nations Program on AIDS (UNAIDS) estimates that at the
end of 2002 nearly 42 million will have died of AIDS.
During 2002, about 3 million people became infected.
AIDS is presently the leading cause of death in Africa and
the fourth leading cause of death worldwide.
Cos P. et al. J. Nat. Prod., 2004, 67, 284-293.
HIV/AIDS as a Global Threat
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HIV-1 Replication CycleHAART – Highly Active AntiRetroviral Therapy
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Problems with the Current Therapy:
- Adverse/Toxic effects.
- High cost of treatment.
- Multiple drug resistance.
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Post-integration processing
U5Cellular DNA
RU3
U3
U5
U3 U3 U5U5
3’-end processing
integraseintegrase
integraseintegrase
HIV-1 DNA
R5’ACTGGAA
3’TGACCTT TAGCAGT 3’ATCGTCA 5’
RU3 gag pol env U3 U5U5
Strand transfer
cytoplasm
nucleus
R5’ACTGGAA
3’ ACCTT TAGCA 3’ATCGTCA 5’
RU3 gag pol env U3 U5U5
Mechanism of HIV-1 DNA integration into a cellular DNA
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HIV-1 integrase:
Catalyzes one of the crucial step of HIV
replication.
Has no cellular analogs.
All retroviral integrases have a
conservative structure.
Is a prospective target for treating HIV infection and preventing AIDS.
HIV-1 Integrase as Anti-HIV Target
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ISTC/BTEP Project # 3197/111
The purpose of the project is to find new
efficient inhibitors of HIV-1 integrase on the
basis of the latest technologies in bioinformatics
and computer-aided drug discovery.
Duration: April 1, 2005 – March 31, 2008
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First Approval of HIV-1 Integrase Inhibitor
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Problems with Finding of HIV-1 Integrase Inhibitors
• Viral strains resistant to HIV-1 integrase inhibitors have been already identified.
• Conformation of integrase is rather flexible, it is stabilized in the pre-integration complex.
• Three-dimensional structure of full-length integrase as well as the structure of integrase complex with viral DNA are not known.
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Participating Institutions
Institute of Biomedical Chemistry of RAMS (IBMC), Moscow (leading organization – computer-aided drug discovery)
Institute of Organic Chemistry of RAS (IOC), Moscow (chemical synthesis of potential compounds)
Institute of Physical-Chemical Biology of MSU (IPCB), Moscow (testing of potential compounds in vitro)
National Cancer Institute, NIH, Frederick, MD (molecular modelling, testing in cell culture)
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ISTC/BTEP Project # 3197/111
Svyatoslav ShevelevIOC RAS (FWS)
Marina GottikhIPCB MSU
Vladimir PoroikovIBMC RAMS
HIV/AIDS
Computer-assisted
discovery of new
HIV-1 integrase
inhibitors
Marc NicklausNCI/NIH
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PASS: Prediction of Activity Spectra for Substances
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What is the Biological Activity Spectrum?
Biological Activity Spectrum is the
“intrinsic” property of the compound that
reflects all kinds of its biological activity,
which can be found in the compound’s
interaction with biological entity.
Poroikov V. and Filimonov D. In: Predictive Toxicology. Ed. by Christoph Helma. Taylor & Francis, 2005, 459-478.
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Biological Activity Spectrum Represents 3300 kinds of biological activity (PASS 2007), including:
374 pharmacotherapeutic effects, e.g.
Alzheimer's disease treatmentAnabolicAnalgesicAngiogenesis inhibitorAngiogenesis stimulantAntiarrhythmicAntiarrhythmic Class IIIAntiarthriticAntibacterial
. . .
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Biological Activity Spectrum Represents 3300 kinds of biological activity (PASS 2007), including:
2755 biochemical mechanisms, e.g.
5 Alpha reductase inhibitor5 Hydroxytryptamine 1 agonist5 Hydroxytryptamine 1A antagonist5 Hydroxytryptamine 1B agonist5 Lipoxygenase inhibitor5-Phytase inhibitor6 Phosphofructokinase inhibitorAcetaldehyde dehydrogenase inhibitorAcetate kinase inhibitorAcetate-CoA ligase inhibitor
. . .
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50 adverse effects & toxicity, e.g.
ArrhythmogenicCarcinogenicCardiotoxicCytotoxicDNA damagingEmbryotoxicEye irritation, corrasiveHematotoxicHyperglycemic
. . .
Biological Activity Spectrum Represents 3300 kinds of biological activity (PASS 2007), including:
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CYP2 substrate
CYP24 substrate
CYP27 substrate
CYP2A substrate
CYP2A1 substrate
CYP2A10 substrate
CYP2A3 substrate
CYP2A6 substrate
. . .
121 metabolic terms, e.g.
Biological Activity Spectrum Represents 3300 kinds of biological activity (PASS 2007), including:
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How Biological Activity Spectrum Is Predicted?
Structure of new compound
O
O
Cl
Cl
An
xio
lyti
cS
ed
ati
ve
5H
T1
A In
hib
itor
Carc
inog
en
. .
.
Estimating the probability that it
has a particular biological activity
Pa Pi for Activity:0.853 0.020 Anxiolytic0.694 0.035 Sedative . . .
Predicted biological activity spectrum
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Some Examples of PASS INet (www.ibmc.msk.ru/PASS) Predictions, Confirmed by the Experiments
Chemical class Biological activity Reference
Methoxyacridines
Antileishmanial Di Giorgio et al., 2003.
Quinazolines Anxiolytic Goel et al., 2005.
Benzimidazoles Antihypertensive Estrada-Soto et
al., 2006.
Polyketides Phosphatase inhibitor Seibert et al., 2006.
Cyclic nitrones Nootropic Marwaha et al., 2007.
Geronikaki A. et al. Prediction of biological activity via Internet. Medicinal chemist's point of view. SAR & QSAR Environ. Res., 2007, 19, 27-38 .
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Lab. Med. Chem., Lab. Str.-Funct. Based NCI, NIH Drug Des., IBMC, RAMS
Computer-assisted mechanism-of-action
analysis of large databases including 250,000 chemical compounds
registered by NCI
Former Collaboration (CRDF Grant RC1-2064)
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More than 64 million PASS predictions included.More than 700 activities available.Predictions separately searchable by probabilities of activity and inactivity.Both types combinable by logical AND.Predictions searchable by probability ranges (in subintervals of 0.0 – 1.0).PASS searches combinable with any other search criteria.
PASS Predictions Searchable in NCI DB Browser (http://cactus.nci.nih.gov)
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Based on PASS predictions, a fraction of “active” compounds can be increased significantly:
Poroikov et al. J. Chem. Inf. Comput. Sci., 2003, 43, 228-236.
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15
10
5
Idea
Medicine
years
Creating New Medicines Is a High Risk Journey
3D-TI Conference, Dec. 10-11, 2007
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General Scheme of Search for New HIV-1 Inhibitors
Computer Screening of Diverse Databases
Development of New Synthetic Routes, Chemical Synthesis
Improvement of PASS Training Set
Molecular Modelling (Target Based Design)
In Vitro Testing
Hits
Testing in Cell Culture
Leads
O P
T I
M I
Z A
T I
O N
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HIV-1 IN Inhibitors Database Prepared for Input to PASS Training Set
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3D Model of HIV-1 Integrase (Karki R. et al. JCAMD, 2004, 18: 739.
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Example of HIV-1 Inhibitors Pharmacophore
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Optimization of the Specialized PASS Training Set
2205 compounds
2006
260 compounds
2008
- Publications
- Patents
- NIAID HIV Therapeutics Database
- Publications (only with Mg2+)
- Tested in NCI
- Tested in IPCB
Name Exp. IC50 , M Predictions (2006 database) Predictions (2008 database)
3’-p ST 3’-p ST 3’-p ST
L-870,810 0.085 0.015 0.589 0.639 0.689 0,765
GS 9137 0.0072 0.485 0,363 0,898
S-1360 0.53 0.193 0.19 0,511
L-870,812 0.04 0,218 0,724
MK-0518 0.007 0,806
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From Hits to Leads: Structure Optimization
GS 9137 MK-0518
IOCh-18-76
IC50: 3’-P = 80 M, ST = 80 M
IOCh-18-47
IOCh-18-74
IC50: 3’-P = 0.2 M, ST = 20 M
IC50: 3’-P = 0.3 M, ST = 0.5 M
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Strand Transfer Inhibition by Compounds IOCh-18-47, IOCh-18-74 and IOCh-18-92
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3’-Processing Inhibition by Compounds IOCh-18-47, IOCh-18-74 and IOCh-18-92
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•198 compounds were selected as hits, synthesized (or purchased from vendors of commercially available samples)
•176 compounds were tested in vitro on inhibition for strand transfer and 32 compounds were tested on inhibition for 3’-processing.
•15 compounds were identified as HIV-1 integrase
inhibiting agents with IC50 values in the micromolar
and sub-micromolar range.
•For 4 most active compounds results were further confirmed by in vitro testing at NCI.
•The discovered compounds belong to the chemical series where this activity was unknown (NCEs).
Summary of the Results
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Some Prospects for a Near Future (BII Supported?)
1. Synthesis and biological testing of additional
rationally designed derivatives from the same
chemical series, to increase potency and
decrease toxicity.
2. Detailed study the mechanism of binding,
specificity, etc. for this classes of compounds.
3. Preparation and submission of patent(s) .
4. Negotiations with pharmaceutical companies
about possibilities of commercialization.
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Acknowledgements
IBMCTamara FedoronchukDmitry FilimonovTatyana GloriozovaDmitry DruzhilovskyAlexey LaguninAlexander ShkrobAlexander Veselovsky
Elena ShilovaAntonina Boudunova
IOCSvyatoslav Shevelev & Associates
IPCBMarina Gottikh & Associates
NCIMarc Nicklaus & AssociatesWinay Pattak & Associates
Financial support: ISTC/BTEP Project # 3197/111