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