Strategies for CADD vary depending on the extent of structural and other information available regarding the target (enzyme/receptor) and the ligands. Computer-aided drug design (CADD) is an exciting and diverse disci...Strategies for CADD vary depending on the extent of structural and other information available regarding the target (enzyme/receptor) and the ligands. Computer-aided drug design (CADD) is an exciting and diverse discipline where various aspects of applied and basic research merge and stimulate each other. In the early stage of a drug discovery process, researchers may be faced with little or no structure activity relationship (SAR) information. The process by which a new drug is brought to market stage is referred to by a number of names most commonly as the development chain or “pipeline” and consists of a number of distinct stages. To design a rational drug, we must firstly find out which proteins can be the drug targets in pathogenesis. In present review we reported a brief history of CADD, DNA as target, receptor theory, structure optimization, structure-based drug design, virtual high-throughput screening (vHTS), graph machines.展开更多
The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/o...The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/or ester bonds through a nucleophilic attack mediated by the catalytic serine residue.SHs are expressed across various mammalian tissues and play critical roles in diverse physiological and pathological processes.展开更多
Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irino...Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.展开更多
KRAS-PDEδinteraction is revealed as a promising target for suppressing the function of mutant KRAS.The bottleneck in clinical development of PDEδinhibitors is the poor antitumor activity of known chemotypes.Here,we ...KRAS-PDEδinteraction is revealed as a promising target for suppressing the function of mutant KRAS.The bottleneck in clinical development of PDEδinhibitors is the poor antitumor activity of known chemotypes.Here,we identified novel spiro-cyclic PDEδinhibitors with potent antitumor activity both in vitro and in vivo.In particular,compound 36 l(KD=127±16 nmol/L)effectively bound to PDEδand interfered with KRAS-PDEδinteraction.It influenced the distribution of KRAS in Mia PaCa-2 cells,downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells.The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX)models.It represents a promising lead compound for investigating the druggability of KRAS-PDEδinteraction.展开更多
The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly ...The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly by two techniques： X-ray crystallog- raphy and nuclear magnetic resonance （NMR） spec- troscopy. Because neither X-ray crystallography nor NMR spectroscopy could directly measure the positions of atoms in a biomolecule, algorithms must be designed to compute atom coordinates from the data. One salient feature of most NMR structure computation algorithms is their reliance on stochastic search to find the lowest energy conformations that satisfy the experimentally- derived geometric restraints. However, neither the cor- rectness of the stochastic search has been established nor the errors in the output structures could be quantified. Though there exist exact algorithms to compute struc- tures from angular restraints, similar algorithms that use distance restraints remain to be developed. An important application of structures is rational drug design where protein-ligand docking plays a crit- ical role. In fact, various docking programs that place a compound into the binding site of a target protein have been used routinely by medicinal chemists for both lead identification and optimization. Unfortunately, de- spite ongoing methodological advances and some success stories, the performance of current docking algorithms is still data-dependent. These algorithms formulate the docking problem as a match of two sets of feature points. Both the selection of feature points and the search for the best poses with the minimum scores are accomplished through some stochastic search methods. Both the un- certainty in the scoring function and the limited sam- pling space attained by the stochastic search contribute to their failures. Recently, we have developed two novel docking algorithms： a data-driven docking algorithm and a general docking algorithm that does not rely on experimental data. Our algorithms search the pose space exhaustively with the pose space itself being limited to a set of hierarchical manifolds that represent, respectively, surfaces, curves and points with unique geometric and energetic properties. These algorithms promise to be es- pecially valuable for the docking of fragments and small compounds as well as for virtual screening.展开更多
文摘Strategies for CADD vary depending on the extent of structural and other information available regarding the target (enzyme/receptor) and the ligands. Computer-aided drug design (CADD) is an exciting and diverse discipline where various aspects of applied and basic research merge and stimulate each other. In the early stage of a drug discovery process, researchers may be faced with little or no structure activity relationship (SAR) information. The process by which a new drug is brought to market stage is referred to by a number of names most commonly as the development chain or “pipeline” and consists of a number of distinct stages. To design a rational drug, we must firstly find out which proteins can be the drug targets in pathogenesis. In present review we reported a brief history of CADD, DNA as target, receptor theory, structure optimization, structure-based drug design, virtual high-throughput screening (vHTS), graph machines.
文摘The serine hydrolase(SH)superfamily,one of the largest enzyme groups in mammals with over 200 members,is characterized by a serine-containing catalytic triad within its active site1.These enzymes hydrolyze amide and/or ester bonds through a nucleophilic attack mediated by the catalytic serine residue.SHs are expressed across various mammalian tissues and play critical roles in diverse physiological and pathological processes.
基金supported by the National Natural Science Foundation of China(Nos.82104281,82273897,and 22367007)China Postdoctoral Science Foundation(Nos.2022M712153,and 2023M742380)+3 种基金The Fundamental Research Funds for Hainan University(KYQD(ZR)23002,China)Hainan Provincial Natural Science Foundation of China(824RC500)PhD Program in Key Fields at Shanghai University of Traditional Chinese Medicine(GJ2023004,China)Liaoning Province Science and Technology Plan Alliance Fund project(2024-BSLH-041,China).
文摘Human carboxylesterase 2A(hCES2A)plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals.Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity(ITGT),but the orally active,selective,and efficacious hCES2A inhibitors are rarely reported.Here,a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design(SBDD)and structural optimization.Initially,donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration(FDA)-approved drugs.Following two rounds of SBDD and structural optimization,a donepezil derivative(B7)was identified as a strong reversible hCES2A inhibitor.Subsequently,nine B7 carbamates were rationally designed,synthesized and biologically assayed.Among all synthesized carbamates,C3 showed the most potent time-dependent inhibition on hCES2A(IC50=0.56 nmol/L),excellent specificity and favorable drug-like properties.C3 could covalently modify the catalytic serine of hCES2A with high selectivity,while this agent also showed favorable safety profiles,high intestinal exposure,and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice.Collectively,this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s),while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.
基金supported by the National Key R&D Program of China(Grant No.2020YFA0509100)the National Natural Science Foundation of China(Grants 21738002,82030105,81725020 and 81903436)。
文摘KRAS-PDEδinteraction is revealed as a promising target for suppressing the function of mutant KRAS.The bottleneck in clinical development of PDEδinhibitors is the poor antitumor activity of known chemotypes.Here,we identified novel spiro-cyclic PDEδinhibitors with potent antitumor activity both in vitro and in vivo.In particular,compound 36 l(KD=127±16 nmol/L)effectively bound to PDEδand interfered with KRAS-PDEδinteraction.It influenced the distribution of KRAS in Mia PaCa-2 cells,downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells.The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX)models.It represents a promising lead compound for investigating the druggability of KRAS-PDEδinteraction.
文摘The three-dimensional structure of a biomolecule rather than its one-dimensionM sequence determines its biological function. At present, the most accurate structures are derived from experimental data measured mainly by two techniques： X-ray crystallog- raphy and nuclear magnetic resonance （NMR） spec- troscopy. Because neither X-ray crystallography nor NMR spectroscopy could directly measure the positions of atoms in a biomolecule, algorithms must be designed to compute atom coordinates from the data. One salient feature of most NMR structure computation algorithms is their reliance on stochastic search to find the lowest energy conformations that satisfy the experimentally- derived geometric restraints. However, neither the cor- rectness of the stochastic search has been established nor the errors in the output structures could be quantified. Though there exist exact algorithms to compute struc- tures from angular restraints, similar algorithms that use distance restraints remain to be developed. An important application of structures is rational drug design where protein-ligand docking plays a crit- ical role. In fact, various docking programs that place a compound into the binding site of a target protein have been used routinely by medicinal chemists for both lead identification and optimization. Unfortunately, de- spite ongoing methodological advances and some success stories, the performance of current docking algorithms is still data-dependent. These algorithms formulate the docking problem as a match of two sets of feature points. Both the selection of feature points and the search for the best poses with the minimum scores are accomplished through some stochastic search methods. Both the un- certainty in the scoring function and the limited sam- pling space attained by the stochastic search contribute to their failures. Recently, we have developed two novel docking algorithms： a data-driven docking algorithm and a general docking algorithm that does not rely on experimental data. Our algorithms search the pose space exhaustively with the pose space itself being limited to a set of hierarchical manifolds that represent, respectively, surfaces, curves and points with unique geometric and energetic properties. These algorithms promise to be es- pecially valuable for the docking of fragments and small compounds as well as for virtual screening.
