Drug Chemical Space as a Guide for New Herbicide Development: A Cheminformatic Analysis

Abstract

Herbicides are critical resources for meeting agricultural demand. While similar in structure and function to pharmaceuticals, the development of new herbicidal mechanisms of action and new scaffolds against known mechanisms of action has been much slower than in pharmaceutical sciences. We hypothesized that this may be due in part to a relative undersampling of possible herbicidal chemistries and set out to test whether this difference in sampling existed and whether increasing the diversity of possible herbicidal chemistries would be likely to result in more efficacious herbicides. To conduct this work, we first identified databases of commercially available herbicides and clinically approved pharmaceuticals. Using these databases, we created a two-dimensional embedding of the chemical, which provides a qualitative visualization of the degree to which each chemotype is distributed within the combined chemical space and shows a moderate degree of overlap between the two sets. Next, we trained several machine learning models to classify herbicides versus drugs based on physicochemical characteristics. The most accurate of these models has an accuracy of 93% with the key differentiating characteristics being the number of polar hydrogens, number of amide bonds, LogP, and polar surface area. We then used several types of scaffold decomposition to quantitatively evaluate the chemical diversity of each molecular family and showed herbicides to have considerably fewer unique structural fragments. Finally, we used molecular docking as an in silico evaluation of further structural diversification in herbicide development. To this end, we identified herbicides with well-characterized binding sites and modified those scaffolds based on similar structural subunits from the drug dataset not present in any commercial herbicide while using the machine-learned model to ensure that required herbicide properties were maintained. Redocking the original and modified scaffolds of several herbicides showed that even this simple design strategy is capable of yielding new molecules with higher predicted affinity for the target enzymes. Overall, we show that herbicides are distinct from drugs based on physicochemical properties but less diverse in their chemistry in a way not governed by these properties. We also demonstrate in silico that increasing the diversity of herbicide scaffolds has the potential to increase potency, potentially reducing the amount needed in agricultural practice.

An analysis of Watson vs. BARD vs. ChatGPT: The Jeopardy! Challenge

“…As noted in Wang et al. (2022), when examining the drug and chemical space, if T > 0.50 then that indicates moderate similarity, while T > 0.70 indicates highly similar and T > 0.90 indicates essentially identical. Other sources (Ucak et al., 2022) suggest that a soft threshold of T ≥ 0.85 has been used to screen similar molecules to determine that the similarity is “high”.…”

“…In that case A = 2, and B = C = 1, and T = 1 / (2 + 1 − 1) = 0.5. The higher the Tanimoto score the more similar the abilities of the systems to provide correct answers to a set of questions. As a result, the Tanimoto score has been used in several contexts and there are some generally accepted interpretations of different thresholds of T. As noted in Wang et al (2022), when examining the drug and chemical space, if T > 0.50 then that indicates moderate similarity, while T > 0.70 indicates highly similar and T > 0.90 indicates essentially identical. Other sources (Ucak et al, 2022) suggest that a soft threshold of T ≥ 0.85 has been used to screen similar molecules to determine that the similarity is "high".…”

Modern Approaches for the Development of New Herbicides Based on Natural Compounds

“…Moreover, in some treatments, the addition of nitrogen fertilizer (ammonium nitrate or ammonium sulfate) to the spray solution increased further the effectiveness of the herbicide in the field [90]. The methylated vegetable oil is known to reduce the surface tension and the contact angle of droplets, but also to prevent their drying, which provided a higher level of penetration of CH into plant tissues, as was shown by the example of topramezone (11) and GY-HMax methylated soybean oil on several weed species [91]. Ammonium fertilizers together with other adjuvants also contribute to more efficient absorption of some herbicides [82,84] After a right selection of adjuvant, the application rate of СН can be considerably reduced.…”

“…The source of information for virtual screening commonly includes chemical structures from published materials or available databases, any commercial or original libraries of synthetic and/or natural compounds. As a rule, specialized sets of drug-like substances are used [11], since some of them possess phytotoxic properties, for example: sulfonamide antibiotics [12], salicylic acid [13], hypotensive [14] and antimalarial substances [15], as well as statins [16]. There are also specialized commercial libraries of herbicide-like compounds [17,18].…”

Modern Approaches for the Development of New Herbicides Based on Natural Compounds

“…The source of information for virtual screening commonly includes chemical structures from published materials or available databases and any commercial or original libraries of synthetic and/or natural compounds. As a rule, specialized sets of drug-like substances are used [ 11 ] since some of them possess phytotoxic properties, for example, sulfonamide antibiotics [ 12 ], salicylic acid [ 13 ], hypotensive [ 14 ], and antimalarial substances [ 15 ], as well as statins [ 16 ]. There are also specialized commercial libraries of herbicide-like compounds [ 17 , 18 ].…”