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Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3- d ]pyrimidine derivatives were rationally designed via scaffold hopping and molecular hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC 50 = 4.44-54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5-5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC 50 = 284 μM) and higher SI values (SI = 5210-63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (sol. = 12.8 μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC 50 = 19.84 μM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.

Targeting the genetic material without destruction is a priority to develop safe anticancer drugs. Histone deacetylase 8 (HDAC8), which is proved to be involved in carcinogenesis, is an enzyme associated with the chromatin for post-translational deacetylation of acetylated lysine. In this study, HDAC8 co-crystallized with the intermediate state tetrapeptide Trapoxin A (TA) inhibitor and the holoenzyme are utilized to find their conformational ensembles. Furthermore, the co-crystallized intermediate gem-diolate TA was used to find optimum interactions with the active site residues by conventional molecular dynamics (MD) simulation and QM/MM umbrella sampling. Finally, the intermediate state of the acetyl-l-lysine substrate was explored by QM/MM steered MD and compared to the binding of the intermediate state of the inhibitor. This research showed that HDAC8 is flexible and exists in conformational ensembles in its holoenzyme state. Binding of the intermediate state TA stabilizes its conformation. The optimum binding to the active site of HDAC8 for structures of gem-diolate TA (intermediate state) and acetyl-l-lysine (intermediate state) was determined according to the corresponding energy profiles. The use of these models will aid in the design of potentially reversible, potent, and selective inhibitors of HDAC8 for cancer treatment.

The HIV-1 CA protein has gained remarkable attention as a promising therapeutic target for the development of new antivirals, due to its pivotal roles in HIV-1 replication (structural and regulatory). Herein, we report the design and synthesis of three series of benzenesulfonamide-containing phenylalanine derivatives obtained by further structural modifications of PF-74 to aid in the discovery of more potent and drug-like HIV-1 CA inhibitors. Structure-activity relationship studies of these compounds led to the identification of new phenylalanine derivatives with a piperazinone moiety, represented by compound 11l , which exhibited anti-HIV-1 NL4-3 activity 5.78-fold better than PF-74 . Interestingly, 11l also showed anti-HIV-2 ROD activity (EC 50 = 31 nM), with almost 120 times increased potency over PF-74 . However, due to the higher significance of HIV-1 as compared to HIV-2 for the human population, this manuscript focuses on the mechanism of action of our compounds in the context of HIV-1. SPR studies on representative compounds confirmed CA as the binding target. The action stage determination assay demonstrated that these inhibitors exhibited antiviral activities with a dual-stage inhibition profile. The early-stage inhibitory activity of compound 11l was 6.25 times more potent as compared to PF-74 but appeared to work via the accelerating capsid core assembly rather than stabilization. However, the mechanism by which they exert their antiviral activity in the late stage appears to be the same as PF-74 with less infectious HIV-1 virions produced in their presence, as judged p24 content studies. MD simulations provided the key rationale for the promising antiviral potency of 11l . Additionally, 11l exhibited a modest increase in HLM and human plasma metabolic stabilities as compared to PF-74 , as well as a moderately improved pharmacokinetic profile, favorable oral bioavailability, and no acute toxicity. These studies provide insights and serve as a starting point for subsequent medicinal chemistry efforts in optimizing these promising HIV inhibitors.

Epigenetic targeting of cancer is a recent effort to manipulate the gene without destroying the genetic material. Lysine-specific demethylase 1 (LSD1) is one of the enzymes associated with the chromatin for post-translational modifications, where it demethylates lysine amino acid in the chromatin H3 tail. Many studies showed that inhibiting LSD1 could potentially be used to treat cancer epigenetically. LSD1 is associated with its corepressor protein CoREST, and it uses tetrahydrofolate as a co-factor to accept CH 2 from the demethylation process. In this study, the co-crystallized co-factor tetrahydrofolate was utilized to determine possible binding regions in the active center of the LSD1/CoREST complex. Also, the flexibility of the complex has been investigated by molecular dynamics simulation and subsequent analysis by clustering and principal component analysis. This research supported other studies and showed that LSD1/CoREST complex exists in two main conformational structures: open and closed. Furthermore, this study showed that tetrahydrofolate stably binds to the LSD1/CoREST complex, in its open conformation, at its entrance. It then binds to the core of the complex, inducing the closed conformation. Furthermore, the interactions of tetrahydrofolate to these two binding regions and the corresponding binding mode of tetrahydrofolate were investigated to be used in structure-based drug design.