Using backend API at: http://localhost:8001 Using LLM provider: openai Backend API test response: 42 == COMPLEX QUERY == What is putative mechanism of action for ENGase inhibitors in the treatment of NGLY-1 deficiency? Starting iterative deepening MCTS with 7 depth iterations == DEPTH ITERATION 1/7 == Running MCTS with 10 iterations from node Query Root Iteration 1 stats: Total nodes explored: 2 Maximum depth reached: 1 Average depth: 1.00 Maximum information gain: 0.80 == DEPTH ITERATION 2/7 == Running MCTS with 10 iterations from node engase inhibitors Running MCTS with 10 iterations from node Query Root Iteration 2 stats: Total nodes explored: 8 Maximum depth reached: 2 Average depth: 2.00 Maximum information gain: 1.60 == DEPTH ITERATION 3/7 == Running MCTS with 10 iterations from node ngly1 deficiency Running MCTS with 10 iterations from node 4.470.44 m Running MCTS with 10 iterations from node 9 Iteration 3 stats: Total nodes explored: 30 Maximum depth reached: 3 Average depth: 2.88 Maximum information gain: 2.40 == DEPTH ITERATION 4/7 == Running MCTS with 10 iterations from node ngly1 Running MCTS with 10 iterations from node studying ngly1 deficiency Running MCTS with 10 iterations from node drug target for treating human ngly1 deficiency Iteration 4 stats: Total nodes explored: 45 Maximum depth reached: 4 Average depth: 3.32 Maximum information gain: 3.20 == DEPTH ITERATION 5/7 == Running MCTS with 10 iterations from node ngly1 gene Running MCTS with 10 iterations from node ngly1-ko cells/animals Running MCTS with 10 iterations from node ngly1/engase double ko cells Iteration 5 stats: Total nodes explored: 53 Maximum depth reached: 5 Average depth: 3.60 Maximum information gain: 4.00 == DEPTH ITERATION 6/7 == Running MCTS with 10 iterations from node 9 Running MCTS with 10 iterations from node n-glycanase enzyme (ngly1) Running MCTS with 10 iterations from node 9 Iteration 6 stats: Total nodes explored: 78 Maximum depth reached: 6 Average depth: 4.47 Maximum information gain: 4.80 == DEPTH ITERATION 7/7 == Running MCTS with 10 iterations from node man9glcnac-thiazoline Running MCTS with 10 iterations from node 4.470.44 m Running MCTS with 10 iterations from node man9glcnac-thiazoline Iteration 7 stats: Total nodes explored: 83 Maximum depth reached: 7 Average depth: 4.59 Maximum information gain: 5.60 == TREE STATISTICS == total_nodes: 83 leaf_nodes: 66 internal_nodes: 17 max_depth: 7 avg_depth: 4.59 max_branching: 10 avg_branching: 7.44 max_info_gain: 5.60 avg_info_gain: 3.47 == IDENTIFIED MULTI-LEVEL EXPLORATION PATHS == Path 1: (Query Root)--(explore)-->(engase inhibitors) Path 3: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors) Path 4: (Query Root)--(explore)-->(engase inhibitors), (engase inhibitors)--(has_IC50)-->(4.470.44 m) Path 5: (Query Root)--(explore)-->(engase inhibitors), (engase inhibitors)--(BELONGS_TO_CLUSTER)-->(9 {description: This cluster focuses on the inhibition of human ENGase (hENGase) by various compounds and the process of drug repurposing. Key studies include the identification of compounds such as Rabeprazole, Lansoprazole, Tenatoprazole, Dexlansoprazole, and Omeprazole as inhibitors of hENGase, with IC50 values ranging from 4.47 µM to ~25.0 µM. The cluster also discusses the use of computational tools like ChemAxon and QikProp for predicting physicochemical properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of these compounds. Additionally, the cluster covers the development of RepurposeDB, a database for drug repurposing that integrates data from various sources and uses chemoinformatics and pharmacological analyses to identify potential drug candidates. The database includes curated drug repositioning examples and provides a systematic analysis of the properties that facilitate successful drug repositioning.}) Path 6: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1) Path 7: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (studying ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1 deficiency) Path 8: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (drug target for treating human ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1 deficiency) Path 9: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1)--(is encoded by)-->(ngly1 gene) Path 10: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1-ko cells/animals)--(SYNTACTIC_CONTAINS)-->(ngly1) Path 11: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1/engase double ko cells)--(SYNTACTIC_CONTAINS)-->(ngly1) Path 12: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1)--(is encoded by)-->(ngly1 gene), (ngly1 gene)--(BELONGS_TO_CLUSTER)-->(9 {description: This cluster focuses on the inhibition of human ENGase (hENGase) by various compounds and the process of drug repurposing. Key studies include the identification of compounds such as Rabeprazole, Lansoprazole, Tenatoprazole, Dexlansoprazole, and Omeprazole as inhibitors of hENGase, with IC50 values ranging from 4.47 µM to ~25.0 µM. The cluster also discusses the use of computational tools like ChemAxon and QikProp for predicting physicochemical properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of these compounds. Additionally, the cluster covers the development of RepurposeDB, a database for drug repurposing that integrates data from various sources and uses chemoinformatics and pharmacological analyses to identify potential drug candidates. The database includes curated drug repositioning examples and provides a systematic analysis of the properties that facilitate successful drug repositioning.}) Path 13: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1)--(is encoded by)-->(ngly1 gene), (ngly1 gene)--(produces)-->(n-glycanase enzyme (ngly1)) Path 15: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1)--(is encoded by)-->(ngly1 gene), (ngly1 gene)--(BELONGS_TO_CLUSTER)-->(9 {description: This cluster focuses on the inhibition of human ENGase (hENGase) by various compounds and the process of drug repurposing. Key studies include the identification of compounds such as Rabeprazole, Lansoprazole, Tenatoprazole, Dexlansoprazole, and Omeprazole as inhibitors of hENGase, with IC50 values ranging from 4.47 µM to ~25.0 µM. The cluster also discusses the use of computational tools like ChemAxon and QikProp for predicting physicochemical properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of these compounds. Additionally, the cluster covers the development of RepurposeDB, a database for drug repurposing that integrates data from various sources and uses chemoinformatics and pharmacological analyses to identify potential drug candidates. The database includes curated drug repositioning examples and provides a systematic analysis of the properties that facilitate successful drug repositioning.}), man9glcnac-thiazoline--(BELONGS_TO_CLUSTER)-->9 Path 16: (Query Root)--(explore)-->(engase inhibitors), (ngly1 deficiency)--(treated with)-->(engase inhibitors), (ngly1 deficiency)--(SYNTACTIC_CONTAINS)-->(ngly1), (ngly1)--(is encoded by)-->(ngly1 gene), (ngly1 gene)--(BELONGS_TO_CLUSTER)-->(9 {description: This cluster focuses on the inhibition of human ENGase (hENGase) by various compounds and the process of drug repurposing. Key studies include the identification of compounds such as Rabeprazole, Lansoprazole, Tenatoprazole, Dexlansoprazole, and Omeprazole as inhibitors of hENGase, with IC50 values ranging from 4.47 µM to ~25.0 µM. The cluster also discusses the use of computational tools like ChemAxon and QikProp for predicting physicochemical properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles of these compounds. Additionally, the cluster covers the development of RepurposeDB, a database for drug repurposing that integrates data from various sources and uses chemoinformatics and pharmacological analyses to identify potential drug candidates. The database includes curated drug repositioning examples and provides a systematic analysis of the properties that facilitate successful drug repositioning.}), 4.470.44 m--(BELONGS_TO_CLUSTER)-->9 == PATH-BASED ANSWER== ENGase (Endo-beta-N-acetylglucosaminidase) inhibitors are being explored as potential treatments for NGLY-1 deficiency, a rare genetic disorder caused by mutations in the NGLY1 gene, which encodes the enzyme N-glycanase 1. This approach is based on the premise that inhibiting the ENGase enzyme could help manage the biochemical imbalances that occur in NGLY-1 deficiency by compensating for the lack of N-glycanase function. 1. **Mechanism of Action**: - ENGase inhibitors target the ENGase enzyme to modulate glycoprotein modifications. This inhibition could potentially prevent the accumulation of misprocessed glycoproteins that happens due to impaired N-glycanase activity in NGLY-1 deficiency (Paths 6, 8, 9, 13). 2. **Trade-offs and Interactions**: - The effectiveness of ENGase inhibitors depends on their potency and selectivity; compounds like Rabeprazole, Lansoprazole, and others have been identified with IC50 values ranging from 4.47 μM to ~25.0 μM, indicating varying degrees of inhibition (Path 5, 12, 15, 16). - These inhibitors must be evaluated for any unintended interaction with other enzymes and pathways, a concern often addressed in drug repurposing analyses (Path 5). 3. **Implications for the Specific Patient Population**: - For patients with NGLY-1 deficiency, ENGase inhibitors represent a novel therapeutic strategy. The goal is to improve cellular glycoprotein processing through indirect modulation, thus potentially alleviating some symptoms and progression of the disease (Path 1, 3). 4. **Overall Safety and Efficacy Considerations**: - The safety and efficacy of ENGase inhibitors need thorough assessment in clinical settings, as suggested by preclinical IC50 data and computational toxicity profiling. The approach may involve using databases like RepurposeDB to identify suitable candidates with favorable ADMET profiles (Path 5, 12, 15, 16). - Balancing efficacy with minimal toxicity is critical, especially for use in sensitive patient populations like those with genetic conditions (Path 9, 11). 5. **Clinical Trial Data**: - While specific clinical trial data was not detailed in the paths, the exploration of existing compounds and computational predictions suggests a pathway toward future clinical investigations. Achieving a safe therapeutic index is pivotal before embarking on clinical trials (Path 5, 16). Overall, ENGase inhibitors hold promise as a potential treatment for NGLY-1 deficiency by intervening in glycoprotein processing pathways. However, further research and clinical evaluations are necessary to substantiate their therapeutic value and safety for patients with this genetic disorder. Each branch explored contributes to understanding these inhibitors' mechanistic and clinical implications, highlighting the complexity and potential of repurposing existing drugs. == REFERENCES == PMC5548696_pdf (Page: 2, 11, 12) PMC7508226_pdf (Page: 1, 2, 7, 12) ChemBioChem - 2018 - Ishii - A New Fluorogenic Probe for the Detection of endo‐ ‐N‐Acetylglucosaminidase_pdf (Page: 1) mvab101_pdf (Page: 1, 2, 3, 4) PMC5398483_pdf (Page: 2, 3, 13)