Molecular design and optimization of hepatic cancer SLP76‐derived PLCγ1 SH3‐binding peptide with the systematic N‐substitution of peptide PXXP motif

A dominant hallmark of living systems is their ability to adapt to changes in the environment by learning and evolving. Nature does this so superbly that intensive research efforts are now attempting to mimic biological processes. Initially this biomimicry involved developing synthetic methods to generate complex bioactive natural products. Recent work is attempting to understand how molecular machines operate so their principles can be copied, and learning how to employ biomimetic evolution and learning methods to solve complex problems in science, medicine and engineering. Automation, robotics, artificial intelligence, and evolutionary algorithms are now converging to generate what might broadly be called in silico-based adaptive evolution of materials. These methods are being applied to organic chemistry to systematize reactions, create synthesis robots to carry out unit operations, and to devise closed loop flow self-optimizing chemical synthesis systems. Most scientific innovations and technologies pass through the well-known “S curve”, with slow beginning, an almost exponential growth in capability, and a stable applications period. Adaptive, evolving, machine learning-based molecular design and optimization methods are approaching the period of very rapid growth and their impact is already being described as potentially disruptive. This paper describes new developments in biomimetic adaptive, evolving, learning computational molecular design methods and their potential impacts in chemistry, engineering, and medicine.

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A Quantitative Metric for Organic Radical Persistence Using Thermodynamic and Kinetic Features

10.26434/chemrxiv.14585934.v1 ◽

2021 ◽

Author(s):

Shree Sowndarya S. V. ◽

Peter St. John ◽

Robert Paton

Keyword(s):

High Performance ◽

Molecular Design ◽

Lone Pair ◽

Feature Space ◽

Organic Radicals ◽

Organic Radical ◽

Ambient Conditions ◽

Design And Optimization ◽

Thermodynamic Stabilization ◽

Solvent Molecules

Long-lived organic radicals are promising candidates for the development of high-performance energy solutions such as organic redox batteries, transistors, and light-emitting diodes. However, “stable” organic radicals that remain unreactive for an extended time and that can be stored and handled under ambient conditions are rare. A necessary but not sufficient condition for organic radical stability is the presence of thermodynamic stabilization, such as conjugation with an adjacent p-bond or lone-pair, or hyperconjugation with a s-bond. However, thermodynamic factors alone do not result in radicals with extended lifetimes: many resonance-stabilized radicals are transient species that exist for less than a millisecond. Kinetic stabilization is also necessary for persistence, such as steric effects that inhibit radical dimerization or reaction with solvent molecules. We describe a quantitative approach to map organic radical stability, using molecular descriptors designed to capture thermodynamic and kinetic considerations. The comparison of an extensive dataset of quantum chemical calculations of organic radicals with experimentally-known stable radical species reveals a region of this feature space where long-lived radicals are located. These descriptors, based upon maximum spin density and buried volume are combined into a single metric, the Radical Stability Score, that outperforms thermodynamic scales based on bond dissociation enthalpies in identifying remarkably long-lived radicals. This provides an objective and accessible metric for used in future molecular design and optimization campaigns. We demonstrate this approach in identifying Pareto-optimal candidates for stable organic radicals.

Download Full-text

A Quantitative Metric for Organic Radical Persistence Using Thermodynamic and Kinetic Features

10.26434/chemrxiv.14585934 ◽

2021 ◽

Author(s):

Shree Sowndarya S. V. ◽

Peter St. John ◽

Robert Paton

Keyword(s):

High Performance ◽

Molecular Design ◽

Lone Pair ◽

Feature Space ◽

Organic Radicals ◽

Organic Radical ◽

Ambient Conditions ◽

Design And Optimization ◽

Thermodynamic Stabilization ◽

Solvent Molecules

Long-lived organic radicals are promising candidates for the development of high-performance energy solutions such as organic redox batteries, transistors, and light-emitting diodes. However, “stable” organic radicals that remain unreactive for an extended time and that can be stored and handled under ambient conditions are rare. A necessary but not sufficient condition for organic radical stability is the presence of thermodynamic stabilization, such as conjugation with an adjacent p-bond or lone-pair, or hyperconjugation with a s-bond. However, thermodynamic factors alone do not result in radicals with extended lifetimes: many resonance-stabilized radicals are transient species that exist for less than a millisecond. Kinetic stabilization is also necessary for persistence, such as steric effects that inhibit radical dimerization or reaction with solvent molecules. We describe a quantitative approach to map organic radical stability, using molecular descriptors designed to capture thermodynamic and kinetic considerations. The comparison of an extensive dataset of quantum chemical calculations of organic radicals with experimentally-known stable radical species reveals a region of this feature space where long-lived radicals are located. These descriptors, based upon maximum spin density and buried volume are combined into a single metric, the Radical Stability Score, that outperforms thermodynamic scales based on bond dissociation enthalpies in identifying remarkably long-lived radicals. This provides an objective and accessible metric for used in future molecular design and optimization campaigns. We demonstrate this approach in identifying Pareto-optimal candidates for stable organic radicals.

Download Full-text