Development of a machine learning‐based target‐specific scoring function for structure‐based binding affinity prediction for human dihydroorotate dehydrogenase inhibitors

Article

作者: He, Zhe ; Zhang, Li ; Tian, Qifeng ; Bao, Wenzhuo ; Feng, Huawei ; Liu, Hongsheng ; Liu, Jinhan ; Hu, Mengfeng ; Meng, Jinhui

AbstractHuman dihydroorotate dehydrogenase (hDHODH) is a flavin mononucleotide‐dependent enzyme that can limit de novo pyrimidine synthesis, making it a therapeutic target for diseases such as autoimmune disorders and cancer. In this study, using the docking structures of complexes generated by AutoDock Vina, we integrate interaction features and ligand features, and employ support vector regression to develop a target‐specific scoring function for hDHODH (TSSF‐hDHODH). The Pearson correlation coefficient values of TSSF‐hDHODH in the cross‐validation and external validation are 0.86 and 0.74, respectively, both of which are far superior to those of classic scoring function AutoDock Vina and random forest (RF) based generic scoring function RF‐Score. TSSF‐hDHODH is further used for the virtual screening of potential inhibitors in the FDA‐Approved & Pharmacopeia Drug Library. In conjunction with the results from molecular dynamics simulations, crizotinib is identified as a candidate for subsequent structural optimization. This study can be useful for the discovery of hDHODH inhibitors and the development of scoring functions for additional targets.

2023-03-01·American Journal of Clinical Dermatology

Pharmacokinetics of Roflumilast Cream in Chronic Plaque Psoriasis: Data from Phase I to Phase III Studies

Article

作者: Thurston, Archie W ; Burnett, Patrick ; Berk, David R ; Snyder, Scott ; Osborne, David W ; Higham, Robert C

BACKGROUNDMost patients with chronic plaque psoriasis receive topical treatment; however, available options lack a balance of efficacy with long-term safety and tolerability. Roflumilast cream 0.3% is a highly potent phosphodiesterase 4 (PDE4) inhibitor approved by the US FDA for treatment of psoriasis.OBJECTIVEThe aim of this study was to define the pharmacokinetic (PK) profile of roflumilast delivered topically from a phase I maximal usage study and data from phase II and phase III studies.METHODSPK data for roflumilast and the active metabolite, roflumilast N-oxide, were determined from a phase I PK and safety maximal usage study of roflumilast cream 0.3% applied once daily for 14 days in patients with plaque psoriasis affecting body surface area (BSA) ≥20% (N = 26). Serial plasma samples were obtained on Days 1 and 15 to determine maximum plasma concentration (C_max) and area under the concentration-time curve (AUC). Plasma concentrations were also assessed at Weeks 3, 4, and 5 for terminal half-life (t_½). Concentrations of roflumilast and roflumilast N-oxide in skin were assessed at Day 28 for 14 patients with psoriasis in a phase I/IIa study of once-daily roflumilast cream 0.5% and 0.15% for 28 days. Systemic exposure (C_trough and AUC) of roflumilast and roflumilast N-oxide in two phase III trials (DERMIS-1, n = 245; DERMIS-2, n = 250) of roflumilast cream 0.3% for 8 weeks was assessed at Weeks 4 and 8.RESULTSBioavailability of roflumilast cream 0.3% after topical administration was 1.5%. Unlike after oral dosing, the plasma concentration-time curve was flat, with a peak-to-trough ratio of 1.2. Roflumilast N-oxide concentrations were eightfold higher than roflumilast concentrations. The t_½ in adult patients was 4.0 days for roflumilast and 4.6 days for roflumilast N-oxide following the last dose administered. Steady state was reached by Day 15. Concentrations of roflumilast in skin were, on average, 126- and 61.8-fold higher than corresponding mean plasma C_trough following administration of roflumilast cream 0.15% and 0.5% daily for 28 days. Roflumilast N-oxide was quantifiable in only one skin sample (N = 27). Following 8 weeks of treatment in DERMIS-1, mean plasma C_trough of roflumilast was 1.78 ng/mL, and 9.86 ng/mL for roflumilast N-oxide. In DERMIS-2, mean plasma C_trough was 1.72 ng/mL and 10.2 ng/mL, respectively. In the maximal usage study (mean BSA: 27.5%), eight patients (30.8%) experienced adverse events (AEs) and all were mild or moderate, with no reports of diarrhea, headache, insomnia, or application-site pain; no patients discontinued treatment due to an AE.CONCLUSIONTopical administration of roflumilast cream 0.3% results in concentrations in skin 126- and 61.8-fold higher relative to plasma, which are much higher than expected to be achievable with oral dosing. PDE4 inhibition in the skin is likely due to roflumilast as compared with its active metabolite, as there is no significant conversion to roflumilast N-oxide in the skin. Consistent with reservoir formation and retention of drug in the stratum corneum, roflumilast is slowly released from the skin (t_½ 4 days) and peak-to-trough ratio is 1.2.CLINICALTRIALSGOV IDENTIFIERSNCT04279119, NCT03392168, NCT04211363, NCT04211389.

2023-03-01·Clinical Pharmacology in Drug Development

A Single‐center, Open‐label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N‐oxide in Healthy Chinese and Caucasian Volunteers

Article

作者: Chen, Shuai ; Wu, Wei ; Zhang, Xin ; Lin, Xiao‐yan ; Lu, Xing ; Li, Jin‐tong ; Mi, Na ; Cui, Gang ; Xiao, Chun‐yan ; Wang, Jing ; Han, Mai

AbstractRoflumilast is a phosphodiesterase‐4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N‐oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 μg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0‐t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0‐t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N‐oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N‐oxide, respectively. Total phosphodiesterase‐4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N‐oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10‐fold higher plasma AUC compared to the parent roflumilast and a much longer observed half‐life, roflumilast N‐oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 μg daily during future clinical trials.

100 项与 Roflumilast N-oxide 相关的药物交易

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