Progress Update: Reimagining the Science Behind
Mechanism-Based Target Selection & Small Molecule Drug Design

A new physics-based, holistic view: bridging cellular systems, atomic-level function, and drug action for smarter medicine.

What Sets Our Theory Apart?

• Top-Down/Bottom-Up Integration: We merge atomic detail (binding, solvation, molecular physics) with cellular network context, recognizing their mutual influence in living systems.
• Real-World Relevance: Focus on drug-target and drug-off-target binding under native physiological conditions—bridging a critical knowledge gap that hinders translation and safety prediction.
• Impactful Science: Our hypotheses and mathematical models, detailed across multiple publications and preprints, shine light on root causes of preclinical and clinical failures, going beyond incremental improvements.

Atomic-level binding in realistic, solvent-filled environments: Water and dynamics matter for prediction!

Newly Accepted! Read our latest J. Med. Chem. Perspective (preprint), rated top 10th–25th percentile in importance.

Rethinking Drug Discovery: Dice Loading and Tossing

Conceptual metaphor—How well do you load the dice before you throw them? (Prediction vs. trial-and-error)

We separate drug discovery into two broad camps:

1. Loading the Dice: Choosing therapeutic targets, hit, and lead molecules to predict “true-positive” clinical candidates—those actually capable of achieving a therapeutic index in humans.
2. Tossing the Dice: Preclinical and clinical testing—the real-world confirmation stage, where loaded dice either land as hoped... or not. Most still fail.

Why Does the Status Quo Fall Short?

• Myth #1: “The sum of the parts equals the whole.” Tacit linearization of cellular systems ignores complex, non-linear feedback—yielding poor human translation (just as linear models fail in planetary, atmospheric, or atomic physics).
• Myth #2: All necessary experimental variables are controlled and relevant. In reality, binding, occupancy, permeability, and in vivo distribution depend critically on unmodeled water molecules, compartmentalization, and solvation physics.
• Dogma vs. Dynamism: “Widely accepted” rules often ignore the key influence of physiological context and non-covalent interactions, leading to selection and optimization pitfalls.

Cellular networks: Everything (really) depends on everything else! Non-linear feedback rules.

The Path Forward: First Principles for Better Medicines

• Descriptive, not just predictive: New theory exposes gaps between observed, predicted, and “real-life” molecular/cellular behavior.
• Push trial-and-error downstream: Prioritize approaches that are intrinsically extrapolatable to human biology, slowing false positives and reducing attrition.
• Prepared minds over lucky guesses: Per Louis Pasteur—progress comes from foundations, not faith in serendipity.
• Intellectual honesty: To quote Neil deGrasse Tyson: “One of the greatest dilemmas in science is knowing enough to think you’re right, but not enough to know you’re wrong.” This quest is ongoing, demanding explicit tests and constant attempts at falsification.

New-generation platforms in action: Bridging chemistry, physics, computation, and systems biology for translational discovery.

There’s no silver bullet or “next big thing” on faith alone—only rigorous science and due diligence propel progress toward effective, safer medicines.