Knowledge of therapeutic targets and early drug candidates is useful for improved drug discovery. In particular, information about target regulators and the patented therapeutic agents facilitates research regarding druggability, systems pharmacology, new trends, molecular landscapes, and the development of drug discovery tools. To complement other databases, we constructed the Therapeutic Target Database (TTD) with expanded information about (i) target-regulating microRNAs and transcription factors, (ii) target-interacting proteins, and (iii) patented agents and their targets (structures and experimental activity values if available), which can be conveniently retrieved and is further enriched with regulatory mechanisms or biochemical classes. We also updated the TTD with the recently released International Classification of Diseases ICD-11 codes and additional sets of successful, clinical trial, and literature-reported targets that emerged since the last update. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. In case of possible web connectivity issues, two mirror sites of TTD are also constructed (http://db.idrblab.org/ttd/ and http://db.idrblab.net/ttd/).

Drug discovery relies on the knowledge of not only drugs and targets, but also the comparative agents and targets. These include poor binders and non-binders for developing discovery tools, prodrugs for improved therapeutics, co-targets of therapeutic targets for multi-target strategies and off-target investigations, and the collective structure-activity and drug-likeness landscapes of enhanced drug feature. However, such valuable data are inadequately covered by the available databases. In this study, a major update of the Therapeutic Target Database, previously featured in NAR, was therefore introduced. This update includes (a) 34 861 poor binders and 12 683 non-binders of 1308 targets; (b) 534 prodrug-drug pairs for 121 targets; (c) 1127 co-targets of 672 targets regulated by 642 approved and 624 clinical trial drugs; (d) the collective structure-activity landscapes of 427 262 active agents of 1565 targets; (e) the profiles of drug-like properties of 33 598 agents of 1102 targets. Moreover, a variety of additional data and function are provided, which include the cross-links to the target structure in PDB and AlphaFold, 159 and 1658 newly emerged targets and drugs, and the advanced search function for multi-entry target sequences or drug structures. The database is accessible without login requirement at: https://idrblab.org/ttd/.

SummaryGenetic modification of plant cell walls has been posed to reduce lignocellulose recalcitrance for enhancing biomass saccharification. Since cellulose synthase (CESA) gene was first identified, several dozen CESA mutants have been reported, but almost all mutants exhibit the defective phenotypes in plant growth and development. In this study, the rice (Oryza sativa) Osfc16 mutant with substitutions (W481C, P482S) at P‐CR conserved site in CESA9 shows a slightly affected plant growth and higher biomass yield by 25%–41% compared with wild type (Nipponbare, a japonica variety). Chemical and ultrastructural analyses indicate that Osfc16 has a significantly reduced cellulose crystallinity (CrI) and thinner secondary cell walls compared with wild type. CESA co‐IP detection, together with implementations of a proteasome inhibitor (MG132) and two distinct cellulose inhibitors (Calcofluor, CGA), shows that CESA9 mutation could affect integrity of CESA4/7/9 complexes, which may lead to rapid CESA proteasome degradation for low‐DP cellulose biosynthesis. These may reduce cellulose CrI, which improves plant lodging resistance, a major and integrated agronomic trait on plant growth and grain production, and enhances biomass enzymatic saccharification by up to 2.3‐fold and ethanol productivity by 34%–42%. This study has for the first time reported a direct modification for the low‐DP cellulose production that has broad applications in biomass industries.