Aug 2026· Chimia (Basel)· Vol 80 7-8, pp.
464-472
· 0 citations· 2 references
Medicine
TL;DR
The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction with physics-based physicochemical property prediction, highlighting neutral polarity as a key determinant of permeability and exposure.
Abstract
This manuscript traces my journey through computational medicinal chemistry, showing how mechanistic and structural insights and physicochemical reasoning enable the translation of challenging targets into drugs and general design principles. The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction. This strategy can unlock dramatic gains in lipophilic efficiency and pharmacokinetic properties through the judicious addition of single atoms. This principle is extended to proteins, particularly kinases, where discrete conformational states can explain binding modes and kinetics. Binding to inactive conformations is linked to slow-on/ slow-off kinetics and can be engineered through ligand design or protein mutations. The manuscript summarizes principles of oral bioavailability in beyond-Rule-of-5 (bRo5) space, highlighting neutral polarity as a key determinant of permeability and exposure. Marketed oral bRo5 drugs and the lead optimization campaigns of first in class representatives converge on a polarity-lipophilicity sweet spot. Finally, nonclassical zwitterions represent a general design strategy to reconcile low lipophilicity with high permeability, supported by strong agreement between computation and experiment.
A structural database that systematically maps the complete activation trajectories of pharmaceutically relevant targets, encompassing TS, IS, and all connecting conformational ensembles is presented, offering multiple strategic advantages for drug discovery.
Molecular dynamics (MD) simulations have become an increasingly important component of modern medicinal chemistry and structure-based drug discovery, providing atomistic insight into protein-ligand interactions that extends beyond static experimental structures and docking models. By explicitly accounting for conformational flexibility, solvent effects, and time-dependent behaviour, MD simulations enable the refinement of binding poses, the identification of transient and allosteric sites, and the quantitative estimation of binding thermodynamics and kinetics, the latter increasingly accessible through Markov state models (MSMs) and milestoning approaches that reconstruct long-timescale behaviour from ensembles of short trajectories. In this mini-review, we provide a practical overview of classical atomistic MD methodologies commonly used in medicinal chemistry, including force-field-based simulations, enhanced sampling techniques, and free-energy calculation methods such as alchemical and end-point approaches. Emphasis is placed on the strengths and limitations of each technique, with particular attention to their appropriate use across different stages of the drug discovery pipeline. We further discuss best practices for system preparation, simulation protocol design, convergence assessment, and reproducibility, highlighting common pitfalls that can lead to overinterpretation of simulation results. Selected examples illustrate how MD simulations have informed medicinal chemistry decisions in lead identification and optimisation. Finally, we briefly outline emerging directions, including the integration of machine learning, ensemble-based approaches, and next-generation force fields, which are expected to further expand the role of MD simulations in medicinal chemistry.
S. S. Çınaroğlu· Mini-Reviews in Medical Chem...· 0 citations
Natural cyclic peptides have long served as a rich reservoir of bioactivity, occupying a unique region of the drug space that bridges the gap between small molecules and large biologics, and researchers are rationally engineering next-generation macrocycles, positioning them at the frontier of modern drug development.
Greta Bergamaschi, Giulia Lodigiani, Stefano Gandolfi et al.· Current Opinion in Chemical...· 0 citations
Macrocyclic peptides are attracting attention as a promising therapeutic modality for addressing intracellular targets that are traditionally difficult to address with conventional small molecules or antibodies. In this study, we present the chemical optimization process behind the development of AUBE00 (AP7400, compound 30), a KRAS-selective inhibitor based on a scaffold similar to LUNA18, an orally bioavailable macrocyclic peptide RAS inhibitor. Achieving KRAS isoform selectivity is exceptionally challenging due to the nearly identical backbone structures of KRAS, HRAS, and NRAS (Cα RMSD < 1.1 Å). The success of this study relied on two critical factors: (1) achieving conformational control of the flexible N-alkyl group through a bridging structure linked to the adjacent side chain, which enabled the exploitation of subtle interaction energy differences among the isoforms; and (2) overcoming the trade-off between improved KRAS selectivity and reduced permeability associated with P-glycoprotein (P-gp) substrate liability by employing a modified Caco-2 membrane permeability assay to recover oral bioavailability. Our results demonstrate that a conformational rigidification through a bridged scaffold, implemented while preserving membrane permeability, is a highly effective strategy for achieving isoform selectivity. This study establishes a generalizable design principle for orally bioavailable macrocyclic peptides targeting intracellular proteins that require mutation or isoform selectivity.
M. Kage, Hatsuo Kawada, Koji Takano et al.· Journal of the American Chem...· 0 citations
This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades to provide a comprehensive view of the evolving cyclic peptide landscape and emerging principles guiding their future development.
T. Thite, Kavita A. Iyer, Preeti Jain et al.· Journal of Medicinal Chemist...· 0 citations
Sulfur occupies a distinct niche in the toolkit of a medicinal chemist. Unlike oxygen, sulfur rationalized by ionic-resonance, negative hyperconjugation into low-lying σ* orbitals, and high polarizability of its 3p valence shell, accommodates the oxidation states from -2 to +6, adopting a diverse range of molecular geometries. Such properties position sulfur as a tunable element that contributes to drug molecules beyond passive lipophilic bulk. The proportion of sulfur-containing motifs among newly FDA-approved small-molecule drugs has increased from approximately 11% in 2020 to about 20% in 2024. Here, we argue that oxidation state switching at a single sulfur atom should be treated as a first-line lead optimization strategy. We map how different oxidation states impact geometry, polarity, and stability and how their interconversion enables rapid tuning of both target engagement and ADMET properties. We analyze synthetic innovations like SuFEx click chemistry, DABSO-mediated sulfonylation, etc., which make these motifs experimentally accessible. We propose a decision-making framework positioning sulfur oxidation state as a dynamic design variable in medicinal chemistry.
Anam Sania Md. Arshad, Rohit Singh, A. Wiemer· Journal of Medicinal Chemist...· 0 citations
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