Allosteric Drug Design

Home ServicesStructure-Based Drug Design (SBDD)Allosteric Drug Design

Overview

Allosteric sites offer what orthosteric sites often cannot: selectivity between close family members, modulation rather than blockade, and activity against targets whose active sites resist drug-like chemistry. They are also harder to find and harder to validate. We identify candidate allosteric pockets through simulation and network analysis, trace the communication pathway that connects a site to the functional centre, and design modulators against sites where the mechanistic case is supportable.

Schematic: structure-based design runs as a loop. Each cycle ends by comparing what was predicted against what the assay actually showed.

Key Advantages

Sites Found Through Dynamics

Allosteric and cryptic pockets frequently appear only in simulation, so detection is driven by molecular dynamics and mixed-solvent mapping rather than by static structure inspection alone.

Communication Pathways Traced

We map how perturbation at the candidate site propagates to the functional site, which distinguishes a genuine allosteric mechanism from an unrelated surface pocket.

Selectivity As The Design Driver

Allosteric sites are typically less conserved than active sites, and we quantify that divergence across the family to show where selectivity can realistically be won.

Direction Of Effect Considered

Designs are assessed for whether they stabilise the active or inactive state, since activators and inhibitors demand different structural strategies.

Where This Service Is Used

Achieving selectivity within a highly conserved target family such as kinases or phosphatases

Finding a tractable site when the orthosteric pocket is shallow, charged or undruggable

Designing activators or positive modulators, which orthosteric approaches rarely deliver

Overcoming resistance mutations located in the orthosteric site

Modulating rather than abolishing function where complete inhibition carries toxicity risk

Methods and Techniques Applied

Extended molecular dynamics with pocket-opening and mixed-solvent analysis to expose transient sites

Allosteric site prediction using structural, dynamic and coevolutionary signals in combination

Communication pathway analysis through dynamic network and correlated motion methods

Conservation analysis across the family to assess selectivity potential at each candidate site

Virtual screening and structure-based design against validated allosteric pockets

Simulation of designed complexes to test conformational effect and the direction of modulation

What We Need From You

Target structure, ideally in more than one conformational state

Functional data indicating which states are active and any known allosteric effectors

Family members against which selectivity is required

Whether inhibition, activation or fine modulation is the therapeutic goal

What You Receive

Ranked allosteric site candidates with dynamic and structural evidence for each

Communication pathway analysis linking each candidate site to the functional centre

Selectivity assessment across the family at each site

Designed or screened modulator candidates with poses and predicted profiles

Mechanistic hypothesis for each design, with the experiment that would test it

What We Compute and Report

Pocket opening frequency and occupancy for transient sites detected in simulation

Communication pathway analysis linking candidate sites to the functional centre

Conservation divergence between the target and family members at each candidate site

Predicted conformational effect of each designed modulator, with direction of modulation

Binding poses and interaction analysis for designed or screened allosteric ligands

Interpretation and Limitations

Computational predictions prioritise hypotheses; they do not independently establish binding, biological activity, therapeutic efficacy, safety or clinical validity. Performance depends on input quality, target class, the structural evidence available and the applicability domain of the selected methods. Scores used for ranking are comparative devices and should not be read as measured quantities. All deliverables are for research use only and are not intended for diagnostic or therapeutic use.

Specifications

Item	Specification	Notes
Typical turnaround	6–12 weeks	Simulation-based site discovery dominates the timeline
Simulation	Multi-µs aggregate	Across replicates and conditions
Sites profiled	3–10 candidates	With the leading sites characterised in full
Design output	Screening hits or de novo designs	Where a site is validated computationally

Service Workflow

Step 01

Scientific Consultation

We discuss the objective, the decision it supports and the data you hold. Nothing is quoted before we understand what the result has to answer.

Step 02

Feasibility Review

We check that the data, target class and available structural evidence can support the proposed approach, and say plainly where they cannot.

Step 03

Technical Proposal

Scope, methods, deliverables, timeline and price are confirmed in writing, together with the limitations we expect to report.

Step 04

Computation and QC

The analysis runs on pinned tool versions in a containerised environment, with quality checkpoints and method comparison where that is informative.

Step 05

Report and Follow-Up

You receive the ranked results, the documented methods, the limitations and a proposed validation plan, plus support in interpreting them.

Is This the Right Service for You?

Choose this service when

Selectivity within a conserved family cannot be achieved at the active site

Modulation rather than complete inhibition is the therapeutic goal

Resistance mutations in the orthosteric site have undermined an inhibitor series

Consider another service when

The orthosteric site is tractable and selectivity is achievable there

High-Throughput Virtual Screening

You only need to know whether any pocket exists

Binding Site & Druggability Assessment

What Goes Wrong, and How We Handle It

The failure modes that produce confident-looking results which do not survive the next experiment. Each one is designed against rather than discovered afterwards.

A communication pathway to the functional centre must be demonstrable before a site is recommended for design.

Case Studies

The situation

Every compound the team made inhibited four family members equally.

What the work involved

Multi-microsecond simulation with mixed-solvent mapping exposed transient pockets, dynamic network analysis traced coupling to the active site, and family conservation was computed per candidate site.

What came back

One pocket coupled to the activation loop and divergent at five positions across the family. Virtual screening against it produced a starting series with measurable selectivity in the first assay round.

Illustrative of the shape this work takes. Details are generalised, no client or target is identified, and scope and outcome vary with the system in question.

Questions We Are Asked Before Scoping

Note: ICDMO delivers computational (in silico) services. Results prioritise hypotheses for testing; they do not by themselves establish binding, biological activity, efficacy or safety. All deliverables are for research use only and are not intended for diagnostic or therapeutic use. Downstream experimental work is scoped separately and executed through qualified partners.

Get in Touch
about Allosteric Drug Design

Tell us about the target, the data you hold and the decision the result needs to support. A scientist reviews every enquiry and replies within one business day.

Feasibility reviewed before any scope or price is fixed

Methods, parameters, confidence and limitations in every report

Confidentiality agreement available before data is shared