A WEB-BASED INFORMATICS PLATFORM FOR PHYSCHEM/ADME/TOX PROPERTY PREDICTIONS Andrius Sazonovas1,2, Kiril Lanevskij1,2, Remigijus Didziapetris,1,2 1. VĹĄÄŽ “AukĹĄtieji algoritmaiâ€?, A. MickeviÄ?iaus 29, LT-08117 Vilnius, Lithuania
2. ACD/Labs, Inc., 8 King Street East, Suite 107, Toronto, Ontario, M5C 1B5, Canada
Introduction
Environment Flexibility/Scalability
ACD/Percepta Portal is a browser-based solution that builds upon the well established components of ACD/Percepta software. It uses the same reliable predictive algorithms for a multitude of physicochemical, ADME, and safety-related properties, powerful data mining, visualization, compound profiling and risk assessment capabilities. It also includes ACD/Structure Design Engine for generating libraries of virtual analogs compatible with the desired characteristics. ACD/Percepta Portal combines these features with flexible network-based deployment, raising software interactivity to a new level and offering some exciting features.
With the server-client architecture and the purely Javascript GUI, requiring nothing but a browser on the user side, ACD/Percepta Portal brings unprecedented accessibility to PhysChem, ADME, and Tox predictions within large corporate environments. The whole software deployment can be scaled to support more/less users and provide more/less Percepta Kernel Server instances for parallel processing by simply manipulating software licenses and several configuration files. All of this allows leveraging the ACD/Percepta Portal in the most dynamic environments with fluctuating numbers of active projects and collaborating partners, where Desktop software cannot compete, primarily due to unacceptable IT overhead (see Scheme 2).
ACD/Percepta Portal Overview
With freely varying substituents, all possible combinations thereof must be eventually tested against whole molecule objectives. In these circumstances, with multiple substitution points analyzed, even an attempt to use modestly sized substituent databases brings the total number of possible combinations to a hefty figure. Despite advanced optimization techniques specifically designed to bring down complexity of this task, exploration of relevant physicochemical space for such virtual libraries is only made possible by the power of parallelized computations available within ACD/Percepta Portal environment.
∆đ?œ‹ đ?‘…1
Project objectives:
R1 min LogP
The ACD/Percepta Portal brings the familiar ACD/Percepta desktop software to a web application that can use high-performance computing (HPC) capabilities, raising the application to a qualitatively higher level. The key aspects of Portal technology are summarized in Scheme 1, while the new features leveraging HPC power are discussed below.
Percepta Desktop
Percepta Portal
O
∆đ?œ‹ đ?‘…4 R4
NH
1
Initial evaluation
Percepta Portal web-application
Everything is conveniently installed, maintained, and updated in a single location.
Regular frequent users
4 −
∆Logđ?‘ƒ =
∆Logđ?‘ƒ+ =
đ?œ‹ đ?‘…1 = 0.00 á 1.00 đ?œ‹ đ?‘…2 = 0.50 á 1.50
Ď€(Rx) and other substituent properties are allowed to take any values given that the above equation holds
đ?œ”đ?‘Ľ ∆đ?œ‹đ?‘šđ?‘Žđ?‘Ľ đ?‘…đ?‘Ľ
đ?œ‹ đ?‘…1 = đ?‘Žđ?‘›đ?‘Ś đ?œ‹ đ?‘…2 = đ?‘Žđ?‘›đ?‘Ś
Starting Log P = 3.00 2 substituents: đ?œ‹ đ?‘…1 = 0.50
đ?œ‹ đ?‘…1 = −1.00 đ?œ‹ đ?‘…2 = 2.00 Log đ?‘ƒ = 2.50
đ?œ‹ đ?‘…2 = 1.00
Target Log P = 2.00  4.00
SCHEME 3. Principles of old (restricted) and new (unrestricted) individual substituent concepts, and an example illustrating how the new engine could avoid missing an analog with a promising overall profile.
MongoDB
Client Side
đ?œ”đ?‘Ľ ∆đ?œ‹đ?‘šđ?‘–đ?‘› đ?‘…đ?‘Ľ
đ?‘Ľ=1
Percepta Portal Communication module
HA Proxy
Unrestricted approach (new)
đ?‘Ľ=1 4
Proportionally distributes the allowed property variance among individual substituents
Custom widgets
STARTING COMPOUND
Network
Server side: flexible framework for integration of in-house models and retrieval of predicted values into 3rd party applications.
Server Side
HO
PROJECT OBJECTIVES Vertical marks on the scales represents the property value of starting compound:
O
MW
Custom DLLs Webservices
Client side: customized GUI widgets support
3
∆Logđ?‘ƒ+ = đ?‘šđ?‘Žđ?‘Ľ Logđ?‘ƒ − Logđ?‘ƒ0
đ?œ‹ đ?‘…1 = −1.00 đ?œ‹ đ?‘…2 = 2.00 Log đ?‘ƒ = 2.50
Ease of Integration
∆LogP +
∆Logđ?‘ƒâˆ’ = đ?‘šđ?‘–đ?‘› Logđ?‘ƒ − Logđ?‘ƒ0
Restricted approach (old) Apache Tomcat
3.00
∆LogP –
O
Front-end Licensing
Purely JavaScript based user interface. No add-ins, works on any platform, any browser.
1.09
-1.00
∆đ?œ‹ đ?‘…3
No. of Users
2
∆đ?œ‹ đ?‘…đ?‘Ľ ≤ ∆Logđ?‘ƒ+ đ?‘Ľ=1
∆đ?œ‹ đ?‘…2 R3
Ease of Deployment and Maintenance
∆Logđ?‘ƒâˆ’ ≤
R2
max LogP
LogP
4
NH
Starting Compound 0 (LogP )
Percepta Kernel Server
Additional frequent/temporary users
KNIME
H3C CH3
Custom Web JAVA API Service API
O
LogP
CH3
O
-1.00
O NH
MW = 789
N
H-Donors
O
Percepta Kernel Server
LogP = 1.09
3.00
NH
CH3
NH
Power of Parallel Computing
O
O
6
NH
ND = 7
9
NA = 18
O
H-Acceptors 15
19
O
Cl
N
900
NH
‌.. PLP
740
HS
N N N N
N
Cl Cl
Cl
H3C
O N
O
N
N
Br
N
N
N N
N
O
N
N O
The architecture relying on multiple calculation units (kernels) can process very large amounts of data in real time
Percepta Kernel Server
Br
O
N
O O
N
O
O
O O
Back to regular usage
O
O
O
N
Virtual server No.5
O N
O
O
N N
O N
Cl O
Cl
N N Cl
N
O
S
O
S N
Virtual server No.4
O
O
N N N
O
O
N F
N
O O
N
S
O
N
N
H
Processing Power
O
N
O
F
H
N
F
N
N
O
Back-end Licensing
O
O
O
O
O
O
S
Virtual server No.1
O O
O
R1
O
Virtual server No.2
O
The workflow can be automated in a Cloud environment so that system adapts to changing demands on the fly
N
N
S
N
N O
O
O
N
O
O O
O
O
O
+
O
O
O N
H
O
NH N
O
N
O
N
N
N
O
N O
S
O
O O O
O O O
N
SCHEME 1. Key features of ACD/Percepta Portal technology.
There are two perspectives from which one may try to assess the cumulative benefits that all these ACD/Percepta Portal architecture features provide – the software flexibility/scalability and the software processing performance
@ACDLabs
info@acdlabs.com
Apart from the trivial fact that parallel processing allows getting everyday calculation jobs done faster, additional computational power has also enabled ACD to review the implementation of some of its well established tools and make them more versatile and more useful. A particular example of such an improvement is the new ACD/Structure Design Engine (SDE). With no restrictions imposed on the properties of an individual substituent, unless specifically set up by the user, each of them is allowed to introduce an arbitrarily large change in a selected property (regardless of the objective for the whole molecule value of that property) as long as it is compensated by the sum of contributions from remaining substituents (see Scheme 3). This approach ensures maximum structural diversity within the pool of theoretically possible analogs and covers candidate structures completely ignored by the standard SDE inside ACD/Percepta Desktop software (see Scheme 4).
www.acdlabs.com
N R
N O
ďƒť ďƒź MW = 150 ďƒź ďƒť ND = 2 ďƒź NA = 5 ďƒź Ď€ = -1.27
HN N N
N
O
Total:
ďƒź MW = 149 ďƒź ďƒť ND = 0 ďƒź NA = 2 ďƒź
R2
O
NH R
O R
CH3
LogP = 1.18 ďƒź
MW = 742
ANALOG NOT CONSIDERED
ďƒź
N R
N O
N
ND = 6
O
ďƒź
ďƒź MW = 150 ďƒź ND = 2 ďƒź NA = 5 ďƒź Ď€ = -1.27
HN
N
N
R4
R
HO
ďƒź MW = 146 ďƒź ND = 0 ďƒź NA = 4 ďƒź Ď€ = 0.41
R3
Ď€ = 1.45
O
ďƒź MW = 142 ďƒź ND = 2 ďƒź NA = 3 ďƒź Ď€ = 0.04
OH
R4
R
HO
ďƒź MW = 146 ďƒť ďƒź ND = 0 ďƒź NA = 4 ďƒź
R1
Ď€ = 0.41
R3
F
O
O
S
Readily Available Processing Power
N
O
O
O
S
O
F
N
O
O
N
O
O
H
F
H
H
O
O
F
O
N
Br
O N
O
O
O H
O
N
N
O
O
Cl
Cl
O
O
O
O
N
Cl
N N
O
O
O
N
NH R
O
N
O
ďƒź MW = 142 ďƒź ND = 2 ďƒź NA = 3 ďƒź Ď€ = 0.04
OH
SCHEME 2. Software scalability comparison between ACD/Percepta Desktop and ACD/Percepta Portal
Virtual server No.3
B
R2
O
O
N
A O
F
N
NH
NA = 18
ďƒź MW = 149 ďƒź ND = 0 ďƒź NA = 2 ďƒź Ď€ = 1.45
O O R
CH3
ďƒź
ANALOG GENERATED
SCHEME 4. Practical example of a different treatment of the identical analogues by the original SDE (A) and the upgraded version from ACD/Percepta Portal (B) under exact same project objectives.
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