Casopitant Mesylate

Published compounds from ChEMBL version 32 are used to seek evidence for the occurrence of "natural selection" in drug discovery. Three measures of natural product (NP) character were applied, to compare time- and target-matched compounds reaching the clinic (clinical compounds in phase 1-3 development and approved drugs) with background compounds (reference compounds). Pseudo-NPs (PNPs), containing NP fragments combined in ways inaccessible by nature, are increasing over time, reaching 67% of clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 clinical versus reference compounds. The majority of target classes show increased clinical compound NP character versus their reference compounds. Only 176 NP fragments appear in >1000 clinical compounds published since 2008, yet these make up on average 63% of the clinical compound's core scaffolds. There is untapped potential awaiting exploitation, by applying nature's building blocks─"natural intelligence"─to drug design.

Neurokinin/tachykinin receptors are classified as the G‐protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three‐dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand–NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets.