Page 84 - IMO-2-3

Innovative Medicines & Omics Synthesis and docking of diorganotin (IV) chelates

including Glu060, Met148, Gly189, Arg220, His257, and penetration. Furthermore, compounds should possess no
Ile020, thereby considerably expanding its interaction more than five hydrogen bond donors and 10 hydrogen
network. These additional contacts are likely to strengthen bond acceptors to ensure good membrane permeability.
binding affinity through a combination of hydrogen The number of rotatable bonds should ideally be 10 or
bonding, electrostatic interactions, and hydrophobic fewer, which contributes to conformational flexibility
effects. Overall, these findings suggest that ligand L-4, and oral bioavailability. Finally, zero to one violation of
followed by L-3, holds significant potential as a promising Lipinski’s rules is generally acceptable for a compound to
antibacterial agent targeting dihydropteroate synthase and be considered drug-like.
transpeptidase enzymes. As shown in Table 8, the four ligands exhibit distinct
3.4. Prediction of drug-likeness of ligands by the drug-likeness profiles, determined by their compliance with
SwissADME tool Lipinski’s rule of five and core physicochemical properties.
The first ligand, L-1, demonstrates excellent drug-like
The SwissADME tool (https://www.swissadme.ch/) properties, with a MW of 325.43, a log P of 4.3, a TPSA
was employed to evaluate the in silico pharmacokinetic of 88.88 Å , four rotatable bonds, and two hydrogen bond
2
properties of ligands L-1 to L-4, with each molecule donors and acceptors, resulting in zero Lipinski violations.
converted into its canonical Simplified Molecular Input The L-2 also complies fully with Lipinski’s criteria, showing
Line Entry System format. The drug-likeness of these a slightly higher log P of 4.83 and MW of 339.45, while
ligands, referring to their potential suitability as orally remaining within acceptable limits for oral bioavailability.
active drugs, was assessed using Lipinski’s rule of five, a In contrast, L-3 exceeds the recommended log P threshold,
widely accepted guideline for predicting oral bioavailability with a value of 5.59, resulting in one Lipinski violation.
based on key physicochemical properties. 37 The While other parameters, such as MW of 387.50 g/mol,
physicochemical properties relevant to ADME profiling TPSA of 88.88 Å , and hydrogen bonding characteristics,
2
include several key parameters (Table 8). An ideal drug are within desirable ranges, the elevated lipophilicity may
candidate typically has a MW of 500 g/mol or less. The log negatively affect its aqueous solubility and absorption.
p-value, representing lipophilicity, should not exceed 5, The fourth ligand, L-4, has a MW of 421.94 g/mol and
as higher values may lead to poor aqueous solubility. The a high log P of 6.22, leading to one Lipinski violation as
topological polar surface area (TPSA) should be 140 Å well. The inclusion of a chlorine atom likely contributes to
2
or less for adequate absorption, with values below 90 Å this increased lipophilicity, which may impair its solubility
2
being particularly favorable for blood-brain barrier (BBB) and pharmacokinetic profile despite acceptable TPSA and

Table 8. Physicochemical, pharmacokinetic, and drug‑likeness properties of ligands (L‑1 to L‑4)
Ligand L‑1 L‑2 L‑3 L‑4
Formula C H N OS C H N OS C H N OS C H ClN OS
18 19 3 19 21 3 23 21 3 23 20 3
Molecular weight (g/mol) 325.43 339.45 387.5 421.94
Log p-value 4.3 4.83 5.59 6.22
Topological polar surface area (Å ) 88.88 88.88 88.88 88.88
2
Rotatable bonds 4 5 5 5
Hydrogen bond donors/acceptors 2/2 2/2 2/2 2/2
Lipinski violations 0 0 1 1
Gastrointestinal absorption High High High High
Blood-brain barrier permeant No No No No
P-glycoprotein substrate No No Yes Yes
CYP1A2 inhibitor Yes Yes No No
CYP2C19 inhibitor Yes Yes Yes Yes
CYP2C9 inhibitor Yes Yes Yes Yes
CYP2D6 inhibitor Yes Yes Yes Yes
CYP3A4 inhibitor Yes Yes Yes Yes
Log Kp skin permeation (cm/s) −5.23 −4.94 −4.69 −4.69
Abbreviation: CYP: Cytochrome P450 enzyme.

Volume 2 Issue 3 (2025) 78 doi: 10.36922/IMO025140019