RIPK1 Modulators Targeting Hydrophobic Pocket for Necroptosis Inhibition
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Solution Overview
Problem
Current RIPK1 inhibitors, such as necrostatins, have limitations including low metabolic stability, off-target effects, suboptimal pharmacokinetics, and modest potency, necessitating the development of novel and improved inhibitors for effectively modulating the RIPK1/RIPK3/MLKL necroptotic pathway.
Innovation Solution
Identification of modulators that interact with specific residues in the hydrophobic pocket of RIPK1, including forming hydrogen bonds with Leu 70 and Ile 154, and hydrophobic interactions with other amino acid residues, using in-silico analysis and molecular docking to select candidate molecules that can inhibit or modulate RIPK1, RIPK3, and MLKL activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If necrostatins are used to inhibit RIPK1, then necroptosis inhibition is achieved, but metabolic stability is low
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of necrostatin compounds to improve metabolic stability while maintaining RIPK1 inhibition efficacy. This involves changing molecular parameters such as adding metabolic stability groups, modifying functional groups, and optimizing molecular weight and lipophilicity to achieve better pharmacokinetic properties without sacrificing the core necroptosis inhibition function.
2Reliability
If necrostatins are used to inhibit RIPK1, then necroptosis inhibition is achieved, but off-target effects occur
Solution Approach 1:
The patent applies local quality by designing compounds with enhanced specificity for the RIPK1 hydrophobic pocket through localized structural modifications. This involves optimizing specific molecular regions that interact with key amino acid residues (such as Leu70, Ile154, and hydrophobic residues) in the RIPK1 binding site, thereby improving selectivity and reducing off-target effects while maintaining potent necroptosis inhibition.
3Reliability
If necrostatins are used to inhibit RIPK1, then necroptosis inhibition is achieved, but pharmacokinetics are suboptimal
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by systematically modifying molecular properties including increasing metabolic stability through structural modifications, optimizing lipophilicity for improved membrane permeability, adjusting molecular weight for better distribution, and enhancing plasma protein binding to prolong half-life. These parameter changes collectively improve the duration of action and overall pharmacokinetic profile while maintaining RIPK1 inhibition efficacy.
4Reliability
If necrostatins are used to inhibit RIPK1, then necroptosis inhibition is achieved, but potency is modest
Solution Approach 1:
The patent enhances inhibition potency through local quality optimization by designing compounds with improved affinity for specific amino acid residues in the RIPK1 hydrophobic pocket. This involves strategic modifications at key interaction sites (such as hydrogen bonding with Leu70 and Ile154, and hydrophobic interactions with residues like Val76, Ala155, Leu90) to maximize binding strength and achieve picomolar to nanomolar potency levels.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The identified modulators, such as Ethinylestradiol, Estradiol, and Estriol, demonstrate potent inhibition of RIPK1 and its downstream targets, offering improved characteristics over existing inhibitors by effectively reducing necroptosis and treating inflammatory and degenerative diseases.
Implementation Method 1
an interaction of said candidate forming a hydrogen bond with amino acid residue Leu 70 of RIPK1
Implementation Method 2
assessing the degree of fit of said three-dimensional structure in the hydrophobic back pocket of RIPK1
Data Source
AI summary
The present invention concerns methods to identify RIPK1 modulators capable of modulating RIPK1 activity, RIPK1 interacting molecules that modulate RIPK1 activity and pharmaceutical compositions comprising RIPK1 modulators.