TY  - JOUR
T1  - When Binding Poses Refuse to Remain Still: A Conformational-Ensemble Theory of Drug–Target Recognition across Dynamic Energy Landscapes
A1  - James Anderson
A1  - Maria Rossi
A1  - William Clark
JF  - International Journal of Pharmaceutical Research and Allied Sciences
JO  - Int J Pharm Res Allied Sci
SN  - 2277-3657
Y1  - 2025
VL  - 14
IS  - 1
DO  - 10.51847/eQVFFtaC7v
SP  - 27
EP  - 34
N2  - Drug–target recognition is often represented by a preferred binding pose and a scalar estimate of binding favorability. These representations are valuable for structural interpretation, but they become pharmacologically incomplete when affinity, selectivity, efficacy, or residence time depends on alternative molecular states, hidden intermediates, transition barriers, allosteric coupling, or condition-dependent population shifts. This article proposes Conformational-Ensemble Drug–Target Recognition theory (CE-DTR), an original conceptual synthesis that represents recognition through five linked layers: baseline molecular ensembles, joint ligand–target compatibility, ligand-conditioned population redistribution, transition pathways, and observable mapping with explicit validation gates. Static poses are treated as informative members of broader ensembles rather than sufficient mechanistic explanations. Conformational selection, ligand-induced change, and mixed recognition are interpreted as pathway-weighted behaviors that may coexist within one energy landscape. The theory separates state occupancy from transition kinetics and distinguishes affinity, selectivity, efficacy, and residence time as related but non-equivalent consequences of ensemble behavior. It generates testable propositions concerning static-pose insufficiency, ligand-driven redistribution, mixed recognition, ensemble-weighted affinity, kinetic bottlenecks, differential selectivity, functional-state coupling, and convergent validation. Computational evaluation requires defensible state definitions, adequate sampling, uncertainty analysis, independent replicas, and comparison with alternative representations. Experimental evaluation requires structural, kinetic, and functional evidence without assuming that agreement at one scale establishes pharmacological performance at another. CE-DTR is proposed as a theory-building framework, not a validated predictive model, clinical recommendation, or universally applicable decision standard. 
UR  - https://ijpras.com/article/when-binding-poses-refuse-to-remain-still-a-conformational-ensemble-theory-of-drugtarget-recogniti-n0hzcsxe3epnhgd
ER  -