Immature Si: I only seek details that make me comfortable while ignoring or downplaying important details that might require me to change course Mature Si: I prepare myself to perform well by methodically learning and attending to every new or significant detail that each situation brings
Immature Ni: I believe I know how the world works though I can’t see myself accurately and don’t know how to live my own life meaningfully Mature Ni: I make positive progress because I possess a deep and meaningful vision of who I should be and what I contribute to the world
Immature Ti: I follow my own rules and principles without really understanding exactly how my actions influence the world at large Mature Ti: I seek precise knowledge of what impact my thoughts/behaviors produce so as to act coherently without harm, bias, or hypocrisy
Immature Fi: I can only see as far as my own values and suffering so I can’t formulate a factual and objective understanding of the world at large Mature Fi: I seek deep understanding of human experience in order to act with integrity and work to prevent/alleviate suffering for myself and others
Immature Se: I simply react as circumstances dictate without enough consideration for whether the direction is the right one to take Mature Se: I seek out new/positive learning experiences and fully appreciate that the unexpected can teach me to be more adaptable to life’s changes
Immature Ne: My mind is unable to conceptualize the best ideas or grasp the most promising opportunities for making progress in life Mature Ne: I am confident in making continual progress because I can work out many viable paths to approach any situation or difficult problem
Immature Te: I utilize power to shape the world into what I want it to be and fail to realize that my actions do not produce universally positive results Mature Te: I utilize my strengths to get positive results for all and work to improve my weaknesses so as to minimize negative or harmful behaviors
Immature Fe: I only care about others in terms of how they affect me and fail to treat them as individuals with their own unique needs/experiences Mature Fe: I can see other people objectively and separately from myself and respond to their needs appropriately and compassionately
aux Si: reflect on how to be content and prioritize accordingly aux Ni: take time to understand every side of an issue accurately aux Ti: acknowledge your flaws and improve systematically aux Fi: reflect on whether your ideas/actions support well-being aux Se: avoid assuming the worst to embrace new experiences aux Ne: work hard to actualize better possibilities for your life aux Te: change any beliefs that prevent success or cause failure aux Fe: improve your relationships and value their feedback
“We learn from failure, not from success!” - Bram Stoker
The developer of Bendy and the Ink Machine is selling official merch. It’s not a lot right now but he discourages buying from unofficial places. Dude just quit his day job to be a full time game dev, so I think he could really use your support.
Quantitative Structure-Activity Relationship (QSARs) - Drug Development
QSAR modelling predicts the biological activity of a compound based off its physical properties. They are used to avoid synthesising and testing every possible version of a molecule to find the optimum for bioactivity. A small number of structurally similar molecules are synthesised and tested, and these results are used to mathematically predict other similar molecules on a computer.
This dictates the ease at which a molecule will pass through a cell membrane. Too hydrophobic and the molecule will be drawn to lipids and its bioactivity will be reduced, too hydrophilic and the molecule will be too polar to pass through the phospholipid bilayer and will not carry out its desired activity (will be excreted in urine)
LogP - a measure of the whole molecule’s hydrophobicity
High logP = more hydrophobic
Low logP = more hydrophillic (polar)
Optimum for bioavailibility = 2-4.5
A regression equation can be formed with c=concentration for max activity
1/c = K1 logP + k2
If linear, values for other similar structures can be taken off the line. If parabolic = logP^2, indicating that after a max concentration bioavalibility will not increase as the drug becomes too hydrophobic and moves into fats.
Substituent hydrophobicity constant,
Measures the hydrophobicity of individual substituents in a compound.
π = logPX - logPH
X= partition coefficient for substituted compound
H= partition coefficient for unsubstituted compound (Hydrogen (so if H was in place of the substituent of interest))
Compares how hydrophobic a substituent is compared to hydrogen
π = +ve –> X= more hydrophobic than hydrogen
π = -ve –> X= less hydrophobic than hydrogen
Note: can be used to calculate logP by adding substituents, rather than having to synthesise and test the molecule (clogP = calculated logP)
Pharmacokinetics (administration, distribution, metabolism and excretion) rarely depends on hydrophobicity alone. The polarity of a compound dictates its passage through the patient and its binding at point of activity.
Hammett substituent constant,
The starting point is a chemical equilibrium for which both the substituent constant and the reaction constant are arbitrarily set to 1: the ionization of benzoic acid (R and R’ both H) in water at 25 °C.
RCO2H <–> RCO2- + H+
uses the dissociation constant
kH = [RCO2-][H+] / [RCO2H]
If X is electron withdrawing, it will stabilise RCO2- and shift the equilibrium to the right.kX will increase
eg NO2, CN, Cl –> +ve
If X is electron donating, it will destabilise the RCO2- anion and shift equilibrium to the left, with a drop in kX.
eg alkyls, ethyls, methyls = -ve σ
σ = logkX - logkH
Taft steric parameter, Es = rate of hydrolysis of XCH2CO2Me under acidic conditions
Es = logkX - logKH
If X is physically small, the rate of hydrolysis (time taken to reach tetrahedral intermediate) will be fast.
Here, the size of R affects the rate of reaction by blocking nucleophilic attack by water.
H 1.24 +ve value: little steric resistance to hydrolysis Me 0.00 the reference substituent in the Taft equation t-Bu -2.78 -ve value: large resistance to hydrolysis
Small X = large Es, large X = small Es
Accuracy of calculation decreases as the bulk and length of the chain increases.
Hansch equations put several of the parameters together to compare overall bioavailibility of different compounds.
Plots 2 constants
functional groups with similar activity will be in the same quadrant
the optimum quadrant, eg +ve
σ and -ve
π, will contain all the substituents worth investigating