ontomine scaffold hop
TRANSCRIPT
Scaffold Hopping using ONTOMINETM
Scaffold Hopping: DefineIt’s a process of designing small molecules against
•Drug Targets•Bio-process/Pathways•Organism Micro biology•Therapeutic indication/disease or phenotype
The goal of scaffold Hopping is that to find chemical patterns representative of NNRT inhibitors and search for potential NNRTI’s in a large database with sufficiently distinct scaffolds andshould be diverse and patentable. Our Insilico approach is satisfying the above criteria successfully,
Some of the characteristics that we looks off on the resultant scaffolds are.
•The molecules should have minimum Drug targets.•It’s should be non-toxic.•It’s should not be promiscuous•It’s should have good Physico chemical (ADME) properties.
Scaffold Hopping-Pattern Development Using Ontomine
Data in Hand and Method:-
5) Training Set : (4 known NNRTI Drugs)
[Delavirdine, Etravirine, Efavirenz, Nevirapine]
2) Test Set : 1 million molecules from Pubchem {Having potential bioactivity profile reported in Pubchem and Pubmed}
3) Scaffold Hopping using Ontomine
4) Validation of Ontomine Hits: NIAID@NIH has Anti-HIV Cellular and Anti-HIV enzyme assay Information.
Distribution of 3297 Categorized “High, Medium, Low” Ontomine Hits
Categorized distribution (High, Medium and Low) of 268 active compounds in a Bio-assay with respect to the 4 known NNRTI compounds
Computational ADMET using ONTOMINETM
Development time and Expense factors in Drug Discovery
The attrition rate is unacceptably high. Only 1 out of 12 drugs entering clinical trials becomes a new drug
Lacking appropriate bioavailability, exhibit poor pharmacokinetics or cause adverse events
With the increasing pressure on reducing animal experiments, Computational toxicology and ADME have an increasingly important role to play.
Why ADME-Tox Prediction?
Ontomine (vHTS & ADMET)
ADMET Physicochemical Property Prediction
Scaffold Hopping
Bio Assay Screening
Active Compound With Good ADMET Features
Ontomine ADMET
The software holds potential to perform high-throughput screening of high dimension chemical compound database on the basis of ADME (Adsorption, Distribution, Metabolism and Excretion) properties for the following predictive values:
•logS•logP•logD•pKa
Predicted Physicochemical Properties
Test Mol - Aspirin
OntoMine ADME predicts physicochemical properties of organic/inorganic compounds at 25 degree C and neutral pH at present.
Ontomine - ADME
Few Example Predictions
Aspirin: Well known analgesic drug
Experimental Values Ontomine-ADME PredictionSolubility: Soluble Solubility: Soluble (logS=-1.42LogP: 1.4 LogP: 1.51Pka: 3.48 Pka: 3.48
Camphor: Chemical used in perfume
Experimental values Ontomine-ADME PredictionSolubility: Soluble Solubility: Soluble (logS=-1.42LogS: -1.98 LogP: 1.51LogP: 2.38 Pka: 3.48
Name Exp_logS
Pred_logS
Exp_logP
Pred_logP
Exp_pKa Pred_pKa
Aspirin -1.59 -1.41 1.19 1.51 3.49 3.45 (Acidic pKa)
Camphor -1.98 -2.55 2.38 2.86 No pKa
Ciprofloxacin -1.04 -0.46 0.28 0.58 6.09 5.33 (Acidic pKa), 7.7 (Base pKa)
Rifampicin -2.77 -3.56 4.24 2.55 6.74 (Acid pKa), 5.65 (Base pKa)
Cloroquine -4.48 -5.16 4.63 4.47 10.1 10.1 (Base pKa)
Few More...
ADME Based Lead OptimizationA Case Study - Curcumin
Principal curcuminoid of the popular Indian spice turmeric
Induce apoptosis in cancer cells
Functional groups characteristic of curcumin scaffold are aromatic ring systems specifically polyphenols that are connected by two α,β-unsaturated carbonyl groups
Curcumin – A Case Study
CurcuminWater InsolublePoor BioavailabilityLimiting its medicinal use for humans when it is taken orally or injected
Obtaining Curcumin analogues
Searching Curcumin – structurally similar molecules in Pubchem retrieves 15697 hits (Searching Criteria : More than 80% similarity)
Finding solubility using Ontomine-ADME
Molecules are grouped based on solubility levelHighly Soluble – 395Soluble – 3555Partially Soluble – 6933Insoluble – 4813
Curcumin 2D Structural Pattern
Solubility LevelConfidence Level
Ontomine-ADME
Bioactivity Studies on curcumin results Tissue-nonspecific alkaline phosphatase precursor InhibitorAnalgesics,NonNarcoticAnti-Rheumatic AgentsAnti-InflammatoryAgents,NonSteroidalEnzyme InhibitorsAnti-Neoplastic Agents
Analogues are explored for Anti-Inflammatory and Anti-Neoplastic activities (Key features of Curcumin)
Analogues are checked for Toxicity using Ontomine-Tox
High Confident Hits with Better ADME Features
Analogue with Priority One Mol ID: 16722486
Solubility: SolublelogP: 4.56Bioactivity: Anti-InflammatoryAgents,NonSteroidal, Anti-Neoplastic AgentsToxicity: No toxicity Predicted
Differ from Curcumin: Added two COOH groups
SMILE: O=C(O)C=2C=C(C=CC(=O)CC(=O)C=CC=1C=C(OC)C(O)=C(C=1)C(=O)O)C=C(OC)C=2(O)
Ranking Analogues based on ADME Features, Bioactivity, and Toxicity
Thank You