In medicinal chemistry, lead optimization is a critically important task and a highly empirical process, largely driven by chemical knowledge and intuition. Only very few approaches are available to guide and evaluate optimization efforts. It is often very difficult to understand when a compound series is exhausted and the generation of additional analogs unlikely to yield further progress toward potent and efficacious candidates. Rationalizing lead optimization remains an essentially unsolved problem. Herein, we introduce a new computational method to aid in evaluating whether sufficient numbers of analogs have been made and further progress is unlikely. The approach integrates the assessment of chemical saturation and structure–activity relationship progression of compound series. Easy-to-calculate scores characterize evolving analog series and identify candidates with high or low priority for further chemical exploration.

Assessing the degree to which analogue series are chemically saturated is of major relevance in compound optimization. Decisions to continue or discontinue series are typically made on the basis of subjective judgment. Currently, only very few methods are available to aid in decision making. We further investigate and extend a computational concept to quantitatively assess the progression and chemical saturation of a series. To these ends, existing analogues and virtual candidates are compared in chemical space and compound neighborhoods are systematically analyzed. A large number of analogue series from different sources are studied, and alternative chemical space representations and virtual analogues of different designs are explored. Furthermore, evolving analogue series are distinguished computationally according to different saturation levels. Taken together, our findings provide a basis for practical applications of computational saturation analysis in compound optimization.

Aim: Combining computational lead optimization diagnostics with analog design and computational approaches for assessing optimization efforts are discussed and the compound optimization monitor is introduced. Methods: Approaches for compound potency prediction are described and a new analog design algorithm is introduced. Calculation protocols are detailed. Results & discussion: The study rationale is explained. Compound optimization monitor diagnostics are combined with a thoroughly evaluated approach for compound design and candidate prioritization. The diagnostic scoring scheme is further extended. Future perspective: Opportunities for practical applications of the integrated computational methodology are described and further development perspectives are discussed.

Predicting compounds with single- and multi-target activity and exploring origins of compound specificity and promiscuity is of high interest for chemical biology and drug discovery. We present a large-scale analysis of compound promiscuity including two major components. First, high-confidence datasets of compounds with multi- and corresponding single-target activity were extracted from biological screening data. Positive and negative assay results were taken into account and data completeness was ensured. Second, these datasets were investigated using diagnostic machine learning to systematically distinguish between compounds with multi- and single-target activity. Models built on the basis of chemical structure consistently produced meaningful predictions. These findings provided evidence for the presence of structural features differentiating promiscuous and non-promiscuous compounds. Machine learning under varying conditions using modified datasets revealed a strong influence of nearest neighbor relationship on the predictions. Many multi-target compounds were found to be more similar to other multi-target compounds than single-target compounds and vice versa, which resulted in consistently accurate predictions. The results of our study confirm the presence of structural relationships that differentiate promiscuous and non-promiscuous compounds.

Small molecules with multitarget activity are capable of triggering polypharmacological effects and are of high interest in drug discovery. Compared to single-target compounds, promiscuity also affects drug distribution and pharmacodynamics and alters ADMET characteristics. Features distinguishing between compounds with single-and multitarget activity are currently only little understood. On the basis of systematic data analysis, we have assembled large sets of promiscuous compounds with activity against related or functionally distinct targets and the corresponding compounds with single-target activity. Machine learning predicted promiscuous compounds with surprisingly high accuracy. Molecular similarity analysis combined with control calculations under varying conditions revealed that accurate predictions were largely determined by structural nearest-neighbor relationships between compounds from different classes. We also found that large proportions of promiscuous compounds with activity against related or unrelated targets and corresponding single-target compounds formed analog series with distinct chemical space coverage, which further rationalized the predictions. Moreover, compounds with activity against proteins from functionally distinct classes were often active against unique targets that were not covered by other promiscuous compounds. The results of our analysis revealed that nearest-neighbor effects determined the prediction of promiscuous compounds and that preferential partitioning of compounds with single-and multitarget activity into structurally distinct analog series was responsible for such effects, hence providing a rationale for the presence of different structure−promiscuity relationships.