Mission Drug Editing

Mission The drug candidate has a poor performance in vivo(inside a body), where it was unable for drug to cross the cell membrane. In this project, I will redesign the drug into orally available, and allow drug to readily cross the membrane. However, note that highlighted functional groups shall not be changed where it is an important compartments for receptor interactions. If changed, the drug candidate will most likely to not have same interaction to the receptor as before, or have low interactions. Before the modification. Lipinski's rule of 1997 Lipinski's rule of 5 is set of checklist for orally available drugs to follow. These are... 1.​ 2.​ 3.​ 4.​ Molecular weight below 500 HBD below 5 HBA below 10 cLogP below 5 Here, the cLogP value represents the partition coefficient ratio between solvents. Following the Lipinski's rule, the Log P value between 0~5 are expected to produce orally compatible drug. This P value is calculated by how much of drug dissolved in 1-octinal over drug dissolved in water(H2O). ~Therefore, with the range acceptable from Log P=0~5, the P value must be in range of 1 to 100 000 . The LogP value for our drug candidate was -1.66 in protonated form. Therefore, we can expect, there are more hydrophilic nature within the drug and should increase our Log P value through drug modification. Veber et al rule from 2002 Another rule for drug to be orally available. 1.​ Polar surface area should be below 140Å 2.​ Should have less than 10 rotatable bond The rotatable bond is crucial for this project, where it can freely rotate on low restriction(this usually happens between free aromatic group), therefore could make unwanted interaction. This could be created by mechanisms such as conformation blocker(will be introduced in dept later) Drug modification As mentioned above, the drug candidate has the Log P value of -1.66, to meet the minimum requirement as a orally available drug, it must be between 0~5 and for an ideal drug, a value between 1.35~1.8. However, our drug must have bit higher than this value since it must penetrate through the membrane(it had claimed the candidate was not able to permeate through the membrane.To increase the permeability, we must add in more hydrophobic (liphophilic). We will expect the drug to be within the range of 1.9~3, the ideal range for liphophilic drug. Trials and Errors Failed trial Attempted to remove non-essential components of the original drug. This allows to remove chirality of the molecule. This technique is used on modification on natural drugs for example modification halichondrin B to eribulin. Additionally, none of the crucial functional group used in bond was not changed. However, the Log P value was recorded as 0.37. Too low to become lipophilic drug. Additionally, there are too much possible free rotation available. This is against the Veber et al rule from 2002 where there should be less then 10 rotatable bonds(So we should still keep some aromatic rings). The amide group was also unprotected from random nucleophilic attack from Final Product Our final product had Log P value of 2.76. Within the range of ideal lipophilic drug. Additionally there were no changes in areas of crucial interactions, as well as molecular weight recording 470.57(<500). Below is a molecular analytics log for the drug candidate built. Steric shield Above is our final product. I have added steric shield(colored in Blue). Steric shield is a mechanisms for drugs more resistant to chemical or enzymatic degradation. Here, I've placed steric shield next to amide group, one of the crucial components of ligand interactions. The amide group is particularly prone to hydrolysis. The addition of the steric shield will hinder the approach of nucleophile, or an enzyme to susceptible group, inhibiting unwanted interactions. The steric shield is usually an addition of bulk of alkyl group. Conformational blocker Notice the Methyl group colored in green, right next to non-basic N, additionally, there's another methyl group added onto the phenol group. This is to inhibit the free rotation of aromatic rings, where it limits the possible conformation for a compound. This is called conformational blocker. Within the biological system, a single bond have a potential to hinder a free rotation. To restrict this a bulk of bulk of methyl substituents will inhibit the rotation through steric clash, and now the aromatic rings(and other functional group) will have rigid structure Here, the non-covalent H-bond perfumers to exists in equilibrium form, where it holds onto each aromatic rings in the same form. Note that rigidification is also possible through intermolecular H-bonding. Addition of polar elements The addition of polar groups had been marked as red in the newly designed drug candidate(N-H). A drug's pharmacokinetics and pharmacodynamics may be significantly impacted by the adding of polar groups to the drug's structure. The solubility, durability, and affinity of a drug molecule for its target can all be affected by polar groups, which are composed of electronegative elements such as oxygen or nitrogen. Next step As our first drug candidate had made up to vivo, but has failed to pass through membrane of test organism(usually test animals, but in rare cases, human specimens are also used). Here, we had designed a new drug with fair range of Log P value, and mechanisms. However, it is not possible for us to jump back into vivo testing, instead, our newly made candidate must pass vitro testing, where chemical testing are done in laboratory environment. vitro tests are used in drug development to study the interactions of potential drug molecules with biological systems, such as cells, tissues, or enzymes.