DEVELOPMENT OF THE

CHEMALYTICS PLATFORM

FOR DRUG DISCOVERY

Gerald J. Wyckoff, UMKC

What drives our research?

The pharmaceutical industry is facing spiraling drug development costs

while R&D productivity remains stalled

6 of the 10 highest-grossing branded products will or have lost patent

exclusivity this year (2014)

Reuters notes that the industry spent $65 billion on drug R&D in the U.S. in

2009, but approval rates have sunk 44% over the past 13 years

Background

Importance of identifying valid targets and therapeutic compounds

Tools currently in use:

Structure-based virtual screening

Receptor-based virtual screening

Other computational tools

Drawbacks to current implementation of high-throughput virtual screening:

Computationally intensive

Limited access due to high cost of infrastructure

Solution:

Virtual screening in the cloud

Provides computational resources scalably and only when needed

Maslow’s Hammer

Chemalytics Platform

Utilizes cloud infrastructure to deliver virtual screening to clients

who either don’t desire to or cannot afford to maintain their

own infrastructure

Highly efficient system for managing job queuing and

maximizing the efficient use of computational resources allows

us to provide reduced-cost access to our tools for academic and

government researchers

“Bucket List” Job Queueing Model

Residual processing power in cloud

Need for low-to-no cost solutions for

academic researchers

Solution: Bucket List model for

job queueing allows unassigned

agents to perform lower-priority

jobs after finishing a paid job

and before “death” at the end

of the provisioned hour

Our Goals in Working with Chemaxon

Integration of additional chemical libraries and library filtering

tools to focus search space prior to docking

Enhancement of end-user ability to evaluate results through

integration of data analysis and visualization tools

Integration of additional licensed, proprietary, and public

domain tools

Outcome:

Products for Three Stages of Drug Discovery

Lead Generation

5 years

Candidate Identification

LeadIdentification

TargetValidation

TargetIdentification

PreclinicalCandidate

Identification PhI / IIa PhIIb PhIII Register

Lead Optimization

3 years

Product Realization

4.5 years

Fingerprinting

Modeling/Docking

Repurposing

Combined Workflow – Chemalytics & Zorilla

Combined Workflow - continued

Zorilla Research, Re-purposing

Zorilla Research, Re-purposing

Front-End Requirements

Spreadsheet-like viewing of compounds

Item Description Source Status

A. Structure identifier. MySQL autogenerated B. Vina Binding energy for mode 0

structure. S3 Project

generated C. Ligand Efficiency -calculated data

from number of heavy atoms in ligand and (B.)

MySQL

calculated

D. Physico-chemical properties calculated by JChem

database precalculated

E. Chemical structure (MarvinView?) MySQL calculated

Visualization Requirements

All numerical fields sortable

Data export as a spreadsheet

Mechanism for 3D view of docked structure

Drill-down for ordering requirements (integration with vendors)

3D Visualization Requirements

Using Jmol

Typical Visualizations

contact connect for 1m14, showing hydrogen

bonds between amino acid residues of a single

chain.

Why We’re Working With Chemaxon

Integration of Marvin and search tools in the web front-end

Consistent nomenclature of all library items

Automated processing of libraries

Future Goals

Build integrated suite of tools (including Zorilla applications)

Improve ancestral protein prediction in phylogenetic analysis

Answer fundamental evolutionary questions relating to

structure/function

For Further Information, contact: wyckoffg@umkc.edu

Acknowledgments

The Wyckoff Lab

Lee Likins, Scott Foy, Ming Yang

Ada Solidar (B-tech Consulting)

HaRo Pharmaceuticals

Tomasz Skorski (Temple University)

The Miziorko Lab (UMKC)

John VanNice

Andrew Skaff

Jeff Murphy (Nickel City Software)

Brian Geisbrecht (K-State)

And his lab

John Walker (SLU)

NIH 1 R41 GM 088922-01A1

NIH 2 R44 GM097902-02A1

NIH 1 R21 AI113552-01

VaSSA Informatics, LLC for major funding

Digital Sandbox KC

Missouri Technology Corporation

UMKC SBS, UMRB, UMKC FRG, KCALSI for additional funding