Ontomine, a US Patent pending software algorithm is used to search for novel non-nucleoside reverse transcriptase inhibitors of HIV.
An sdf database of about 900,000 small molecules from pubchem is screened using information derived from 4 well known inhibitors.
It is shown that the results are novel, highly accurate with reference to known biological activity from assays and that the method is better than docking.
Ontomine based scaffold hopping identifies diverse molecules starting with a few known drugs and can be used instead of OR alongside docking methodologies.
8. 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)
9. ADMET Physicochemical Property Prediction Scaffold Hopping Bio Assay Screening Active Compound With Good ADMET Features Ontomine ADMET
10.
11. Few Example Predictions Aspirin: Well known analgesic drug Experimental Values Ontomine-ADME Prediction Solubility: Soluble Solubility: Soluble (logS=-1.42 LogP: 1.4 LogP: 1.51 Pka: 3.48 Pka: 3.48 Camphor: Chemical used in perfume Experimental values Ontomine-ADME Prediction Solubility: Soluble Solubility: Soluble (logS=-1.42 LogS: -1.98 LogP: 1.51 LogP: 2.38 Pka: 3.48
14. 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 Curcumin Water Insoluble Poor Bioavailability Limiting its medicinal use for humans when it is taken orally or injected
15. 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 level Highly Soluble – 395 Soluble – 3555 Partially Soluble – 6933 Insoluble – 4813
17. Bioactivity Studies on curcumin results Tissue-nonspecific alkaline phosphatase precursor Inhibitor Analgesics,NonNarcotic Anti-Rheumatic Agents Anti-InflammatoryAgents,NonSteroidal Enzyme Inhibitors Anti-Neoplastic Agents Analogues are explored for Anti-Inflammatory and Anti-Neoplastic activities (Key features of Curcumin) Analogues are checked for Toxicity using Ontomine-Tox
19. Analogue with Priority One Ranking Analogues based on ADME Features, Bioactivity, and Toxicity Mol ID: 16722486 Solubility: Soluble logP: 4.56 Bioactivity: Anti-InflammatoryAgents,NonSteroidal, Anti-Neoplastic Agents Toxicity: 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)