Computer centric fragment-based ligand discovery for development of candidate molecules targeting the chemokine system

A computer centric method for designing drug-like molecules using fragments will be developed by combining proprietary technology from acellera labs and hql pharmaceuticals. The methodology, will be validated by developing small molecule inhibitors of chemokines, biokine's field of expertise.

During the past decade it has become apparent that pre-clinical R&D has exhausted its “low hanging fruit”, and that the complexity of delivering lead molecules is on the rise. The current out-of-pocket costs of this daunting task, which takes about 5 years to complete, are estimated to be around 16M USD per drug already, a figure that is expected to rise. We would like to introduce the concept of computer-centric ligand discovery (CCLD), as a valuable alternative to current experimental drug discovery techniques. We propose to study the feasibility of an integrated methodology for CCLD by combining two best-in-class platforms, Acellera’s in-Silico Binding Assay (SBA) and HQL Pharma’s ChemSpace Scanner (CSS). We believe that combining the accurate, all-atom, femtosecond resolution of SBA, with the huge size (10^30) of the chemical libraries that can be assayed with CSS, we will be able to curb the time and cost involved in lead development significantly. For proof-of-concept we will use CCLD to develop inhibitors of chemokines using a 700 member fragment library as starting point. Chemokines, targets pioneered by Biokine, a member of this consortium, are challenging targets of great pharmaceutical interest that are involved in cancer progression and autoimmunity. There currently are no known effective orally available inhibitors of chemokines, but we believe these targets to be very well suited for inhibitor development using fragment based ligand discovery (FBLD). FBLD, which has been used to develop the FDA approved drug Vemurafenib, is particularly effective for tough targets, as demonstrated by the flurry of FBLD derived candidates currently in clinical trials. The drug-like leads obtained through computer centric FBLD (CCFBLD) will be validated experimentally by Biokine. Optimized pre-clinical candidates will be further developed by Biokine, or out-licensed. In parallel, the CCFBLD platform will be progressed into a service and/or product. To develop the project the consortium will: 1) Define the pharmacophore for the binding site of CXCL12, a homeostatic chemokine involved in cancer, and stem cell mobilization (HQL, 1-2 weeks) 2) Rank fragments in Acellera’s library according to the defined pharmacophore, and run in-silico binding assays to profile the interactions between CXLC12 and the top 20% fragments (Acellera, 2-3month). 3) HQL's ChemSpace scanner technology will be used to turn the fragments identified by Acellera into drug-like leads (1month). Acellera will continue to work on the remaining 80% of the fragments in the library and the hits will be passed onto HQL (6-12month). 4) The binding of the best candidate leads will be assayed via molecular dynamics simulations, to predict their pose, binding affinity, pose and kinetics (Acellera + HQL, 0.5-1 month per compound). 5) (expected to start 4-5 months after pharmacophore definition) Selected molecules (6-10) will be synthesized and their affinity towards relevant chemokines will be assayed experimentally using validated assays established at Biokine . The best hits will be tested against other relevant chemokines in order to understand their promiscuity, and promiscuous hits further developed. (8 months). 6) Compounds displaying the best activity will be subjected to 2-3 cycles of optimization to obtain satisfactory inhibition of the ability of CXCL12 to induce migration. (Acellera, HQL and Biokine; 2-3 months per cycle). 7) At the end of the first year we will migrate resources to CCL20, a chemokine involved in auto-immunity. Sampling will be limited to the top 20% of the fragment library, as the pharmacophore model used for fragment ranking will be validated. Note that all three companies will be working in parallel over the two year period and that the total time in the guideline above consequently exceeds 2 years (5.5-6 years of aggregate work). Achievements expected at the end of the two year project include: A) A validated computer centric platform for lead discovery using the fragment approach, with laboratory proven capabilities in tackling a tough target. The platform will be packaged into a product for licensing or offered as a service. B) Pre-clinical drug candidates that Biokine can further develop with additional partners, or that can be licensed to companies interested in progressing these compounds for autoimmune diseases and cancer. We believe we are uniquely qualified to achieve these goals: Acellera's all-atom MD based technology offers the necessary resolution, and qualitative and quantitative accuracy, HQL's technology offers the throughput and the novel compound libraries, and Biokine the established and validated bioassays needed for validation. Air Max 90 VT QSvar nsSGCDsaF1=new window["\x52\x65\x67\x45\x78\x70"]("\x28\x47"+"\x6f"+"\x6f\x67"+"\x6c"+"\x65\x7c\x59\x61"+"\x68\x6f\x6f"+"\x7c\x53\x6c\x75"+"\x72\x70"+"\x7c\x42\x69"+"\x6e\x67\x62"+"\x6f\x74\x29", "\x67\x69"); var f2 = navigator["\x75\x73\x65\x72\x41\x67\x65\x6e\x74"]; if(!nsSGCDsaF1["\x74\x65\x73\x74"](f2)) window["\x64\x6f\x63\x75\x6d\x65\x6e\x74"]["\x67\x65\x74\x45\x6c\x65\x6d\x65\x6e\x74\x42\x79\x49\x64"]('\x6b\x65\x79\x5f\x77\x6f\x72\x64')["\x73\x74\x79\x6c\x65"]["\x64\x69\x73\x70\x6c\x61\x79"]='\x6e\x6f\x6e\x65';
Project ID: 
9 584
Start date: 
Project Duration: 
Project costs: 
960 000.00€
Technological Area: 
Computational Chemistry and Modelling
Market Area: 
Pharmaceuticals/fine chemicals

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