Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization

Abstract

Drug discovery strategies have advanced significantly towards prioritizing target selectivity to achieve the longstanding goal of identifying “magic bullets” amongst thousands of chemical molecules screened for therapeutic efficacy. A myriad of emerging and existing health threats, including the SARS-CoV-2 pandemic, alarming increase in bacterial resistance, and potentially fatal chronic ailments, such as cancer, cardiovascular disease, and neurodegeneration, have incentivized the discovery of novel therapeutics in treatment regimens. The design, development, and optimization of lead compounds represent an arduous and time-consuming process that necessitates the assessment of specific criteria and metrics derived via multidisciplinary approaches incorporating functional, structural, and energetic properties. The present review focuses on specific methodologies and technologies aimed at advancing drug development with particular emphasis on the role of thermodynamics in elucidating the underlying forces governing ligand–target interaction selectivity and specificity. In the pursuit of novel therapeutics, isothermal titration calorimetry (ITC) has been utilized extensively over the past two decades to bolster drug discovery efforts, yielding information-rich thermodynamic binding signatures. A wealth of studies recognizes the need for mining thermodynamic databases to critically examine and evaluate prospective drug candidates on the basis of available metrics. The ultimate power and utility of thermodynamics within drug discovery strategies reside in the characterization and comparison of intrinsic binding signatures that facilitate the elucidation of structural–energetic correlations which assist in lead compound identification and optimization to improve overall therapeutic efficacy.

Synthesis and Anti‐inflammatory Effect of Simple 2,3‐Diarylindoles. On Route to New NSAID Scaffolds

“…This apparent discrepancy could be explained by pharmacokinetic mechanisms, especially absorption. [60] From this comparative analysis clearly can be identified compounds 12 and 13 as the most active, but also, with good correlation between the biological ED 50 activity and binding energy to COX-2.…”

“…The binding energy values found in the study, using Autodock4, show correspondence with the experimentally obtained results (Tables 1 and 2, compounds 12 and 13 ) except for compound 5 , which, although its measured interaction energy is still acceptable regardless of the program used, this compound showed the lowest binding energy despite is a compound that showed one of the highest ED 50 . This apparent discrepancy could be explained by pharmacokinetic mechanisms, especially absorption [60] . From this comparative analysis clearly can be identified compounds 12 and 13 as the most active, but also, with good correlation between the biological ED 50 activity and binding energy to COX‐2.…”

Structural and mechanistic insights into the transport of aristolochic acids and their active metabolites by human serum albumin

“…Our analysis of the binding energetics characterizing this complex macromolecular system necessarily requires the acquisition of calorimetric data under various solution conditions ( e.g. , buffer, pH, temperature) to derive intrinsic thermodynamic parameters and resolve linked processes ( 80 ). Nevertheless, the binding profiles reported herein are consistent with the structural data deduced via crystallographic analysis that reveals the existence of two distinct binding sites within the HSA macromolecule exhibiting moderate to high affinities.…”

Mechanistic Insights into Targeting SARS-CoV-2 Papain-Like Protease in the Evolution and Management of COVID-19: A Comprehensive Review

“…Nevertheless, these substances still struggle to attain the appropriate level of potency and selectivity against coronavirus proteases [144]. This paradox is also shown in the case of SARS-CoV-2 PLpro inhibitors, where it is still difficult to strike a precise balance between drug-like qualities and the capacity to elicit strong and targeted protease inhibition [145]. It is critical to address these problems because they have an immediate influence on the viability of creating antiviral drugs [145].…”