Cytochrome P450 (CYP450) enzymes belong to a superfamily of heme-containing proteins that are involved in the metabolism of structurally diverse endogenous and exogenous compounds. Various proof-of-concept studies indicate that metabolic stability and intrinsic clearance of CYP450 substrates are linked with the respective lipophilicity (log P or log D). This necessitates the normalization of lipophilicity (log P or log D) of a given CYP450 substrate with respect to its metabolic stability (LipMetE) and intrinsic clearance (log 10 CL int,u ). Therefore, in this article, the LipMetE values of already known substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, including some marketed drugs, have been calculated to elucidate the relationship between lipophilicity (log D 7.4 ) and in vitro clearance. Moreover, various drug efficiency metrics including lipophilic efficiency (LipE) and ligand efficiency (LE) have been evaluated, and the thresholds of these parameters have been defined for the CYP450 substrates exhibiting normalized LipMetE. Our results indicate that for a given range of LipMetE, greater the log D value of the substrate the more avidly it binds to a given CYP450 enzyme and shows more intrinsic clearance (log 10 CL int,u ). Overall, the majority of the model substrates of CYP450 isoforms and already marketed drugs in our datasets exhibit log D 7.4 values of ∼2.5 with LipMetE values in the range of 0−2.5 and LipE values of ≤3. Overall, consideration of these parameters in ADME profiling could aid in reducing the drug failure rate in the later stages of clinical investigations.

Coronavirus disease 2019 (COVID-19) is an infectious disease characterised by symptoms that are like the common cold. The current pandemic situation in anticipation of a vaccine has posed serious threats to the health and economic sectors of countries worldwide. To overcome the quick transmission of the virus, the government of Australia has also taken drastic measures to prevent its spread. These policies include an international and interstate travel ban, social distancing rules, lockdown, shutdown of educational institutes and work-from-home policies. Such rules have affected people on both behavioural and psychological levels. This study aims to analyse the effect of COVID-19 on Australian citizens, and therefore, the changed behaviour of citizens concerning their mobility patterns, transport preferences and shopping methods under the pandemic have been studied. A detailed literature search was adopted for gathering data related to the study theme, along with real-time evidence of changes in the behaviour of people following the pandemic. The socioeconomic impact of the pandemic on social inequality and thereby the effect on the vulnerable people of the population are also studied. Authentic surveys and statistical data are consulted to figure out how the new lifestyle choices of people will linger in the post-pandemic era. It was found that people in Australia have adopted the work-from-home regime, and new habits suiting the nationwide restrictions have become routine for many people.

The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects.

The expression of the drug efflux pump ABCB1 correlates negatively with cancer survival, making the transporter an attractive target for therapeutic inhibition. In order to identify new inhibitors of ABCB1, we have exploited the cryo-EM structure of the protein to develop a pharmacophore model derived from the best docked conformations of a structurally diverse range of known inhibitors. The pharmacophore model was used to screen the Chembridge compound library. We identified six new potential inhibitors with distinct chemistry compared to the third-generation inhibitor tariquidar and with favourable lipophilic efficiency (LipE) and lipophilicity (CLogP) characteristics, suggesting oral bioavailability. These were evaluated experimentally for efficacy and potency using a fluorescent drug transport assay in live cells. The half-maximal inhibitory concentrations (IC50) of four of the compounds were in the low nanomolar range (1.35 to 26.4 nM). The two most promising compounds were also able to resensitise ABCB1-expressing cells to taxol. This study demonstrates the utility of cryo-electron microscopy structure determination for drug identification and design.

The cytochrome P450s (CYPs) play a central role in the metabolism of various endogenous and exogenous compounds including drugs. CYPs are vulnerable to inhibition and induction which can lead to adverse drug reactions. Therefore, insights into the underlying mechanism of CYP450 inhibition and the estimation of overall CYP inhibitor properties might serve as valuable tools during the early phases of drug discovery. Herein, we present a large data set of inhibitors against five major metabolic CYPs (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) for the evaluation of important physicochemical properties and ligand efficiency metrics to define property trends across various activity levels (active, efficient and inactive). Decision tree models for CYP inhibition were developed with an accuracy >90% for both the training set and 10-folds cross validation. Overall, molecular weight (MW), hydrogen bond acceptors/donors (HBA/HBD) and lipophilicity (clogP/logPo/w) represent important physicochemical descriptors for CYP450 inhibitors. However, highly efficient CYP inhibitors show mean MW, HBA, HBD and logP values between 294.18–482.40,5.0–8.2,1–7.29 and 1.68–2.57, respectively. Our results might help in optimization of toxicological profiles associated with new chemical entities (NCEs), through a better understanding of inhibitor properties leading to CYP-mediated interactions.