Deep neural network modeling based virtual screening and prediction of potential inhibitors for renin protein.

Renin enzyme plays an essential role in the Renin-Angiotensin System (RAS), and it is involved in the pathogenesis of hypertension and several other cardiovascular diseases (CVDs). Inhibition of renin is an effective way to intervene with the pathogenesis of these diseases. Docking-based virtual screening, 3D-Quantitative Structure-Activity Relationship (3D-QSAR), and structure-based drug design are the most frequently used strategies towards discovering novel inhibitors targeting renin. In this study, we have developed a 2D fingerprint-based Deep Neural Network (DNN) classifier for virtual screening and a DNN-QSAR model for biological activity prediction. The resulting hits from the DNN-QSAR model were then subjected to the molecular docking to identify further top hits. Molecular Dynamics (MD) simulation was conducted to get a better insight into the binding mode of identified hits. We have discovered six compounds from the Maybridge chemical database with the predicted IC50 values ranging from 24.2 nM to 83.6 nM. To the best of our knowledge, this is the first study that used a cascaded DNN model to identify potential lead compounds for the inhibition of renin target. Through the results presented in this study, we provide evidence of the DNN method being a useful approach to identify new chemical entities/novel lead compounds that may overcome the limitation of existing conventional strategies used in drug discovery research.Communicated by Ramaswamy H. Sarma.

Synthesis and Evaluation of Galloyl Conjugates of Flavanones as BMP-2 Upregulators with Promising Bone Anabolic and Fracture Healing Properties.

The molecular hybridization concept led us to design a series of galloyl conjugates of flavanones that have potent osteoblast differentiation ability in vitro and promote bone formation in vivo. An array of in vitro studies, especially gene expression of osteogenic markers, evinced compound 5e as the most potent bone anabolic agent, found to be active at 1 pM, which was then further assessed for its osteogenic potential in vivo. From in vivo studies on rat calvaria and a fracture defect model, we inferred that compound 5e, at an oral dose of 5 mg/(kg day), increased the expression of osteogenic genes (RUNX2, BMP-2, Col1, and OCN) and the bone formation rate and significantly promoted bone regeneration at the fracture site, as evidenced by the increased bone volume/tissue fraction compared with vehicle-treated rats. Furthermore, structure-activity relationship studies and pharmacokinetic studies suggest 5e as a potential bone anabolic lead for future osteoporosis drug development.

Therapeutic potential of phosphodiesterase inhibitors in the treatment of osteoporosis: Scopes for therapeutic repurposing and discovery of new oral osteoanabolic drugs.

Cyclic nucleotide phosphodiesterases (PDEs) are ubiquitously expressed enzymes that hydrolyze phosphodiester bond in the second messenger molecules including cAMP and cGMP. A wide range of drugs blocks one or more PDEs thereby preventing the inactivation of cAMP/cGMP. PDEs are differentially expressed in bone cells including osteoblasts, osteoclasts and chondrocytes. Intracellular increases in cAMP/cGMP levels in osteoblasts result in osteogenic response. Acting via the type 1 PTH receptor, teriparatide and abaloparatide increase intracellular cAMP and induce osteoanabolic effect, and many PDE inhibitors mimic this effect in preclinical studies. Since all osteoanabolic drugs are injectable and that oral drugs are considered to improve the treatment adherence and persistence, osteogenic PDE inhibitors could be a promising alternative to the currently available osteogenic therapies and directly assessed clinically in drug repurposing mode. Similar to teriparatide/abaloparatide, PDE inhibitors while stimulating osteoblast function also promote osteoclast function through stimulation of receptor activator of nuclear factor kappa-B ligand production from osteoblasts. In this review, we critically discussed the effects of PDE inhibitors in bone cells from cellular signalling to a variety of preclinical models that evaluated the bone formation mechanisms. We identified pentoxifylline (a non-selective PDE inhibitor) and rolipram (a PDE4 selective inhibitor) being the most studied inhibitors with osteogenic effect in preclinical models of bone loss at ≤ human equivalent doses, which suggest their potential for post-menopausal osteoporosis treatment through therapeutic repurposing. Subsequently, we treated pentoxifylline and rolipram as prototypical osteogenic PDEs to predict new chemotypes via the computer-aided design strategies for new drugs, based on the structural biology of PDEs.

A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss.

Chronic alcoholism (CA) decreases bone mass and increases the risk of hip fracture. Alcohol and its main metabolite, acetaldehyde impairs osteoblastogenesis by increasing oxidative stress. Aldehyde dehydrogenase (ALDH) is the rate-limiting enzyme in clearing acetaldehyde from the body. The clinical relevance of ALDH in skeletal function has been established by the discovery of single nucleotide polymorphism, SNP (rs671) in the ALDH2 gene giving rise to an inactive form of the enzyme (ALDH2*2) that causes increased serum acetaldehyde and osteoporosis in the affected individuals. Subsequent mouse genetics studies have replicated human phenotype in mice and confirmed the non-redundant role of ALDH2 in bone homeostasis. The activity of ALDH2 is amenable to pharmacological modulation. ALDH2 inhibition by disulfiram (DSF) and activation by alda-1 cause reduction and induction of bone formation, respectively. DSF also inhibits peak bone mass accrual in growing rats. On the other hand, DSF showed an anti-osteoclastogenic effect and protected mice from alcohol-induced osteopenia by inhibiting ALDH1a1 in bone marrow monocytes. Besides DSF, there are several classes of ALDH inhibitors with disparate skeletal effects. Alda-1, the ALDH2 activator induced osteoblast differentiation by increasing bone morphogenic protein 2 (BMP2) expression via ALDH2 activation. Alda-1 also restored ovariectomy-induced bone loss. The scope of structure-activity based studies with ALDH2 and the alda-1-like molecule could lead to the discovery of novel osteoanabolic molecules. This review will critically discuss the molecular mechanism of the ethanol and its principal metabolite, acetaldehyde in the context of ALDH2 in bone cells, and skeletal homeostasis.

Identification of potential soluble epoxide hydrolase (sEH) inhibitors by ligand-based pharmacophore model and biological evaluation.

Communicated by Ramaswamy H. Sarma.

Molecular modeling assisted identification and biological evaluation of potent cathepsin S inhibitors.

Cathepsin S (CatS) is one of the cysteinyl cathepsins widely studied for its clinical significance and found to be a promising therapeutic target for several diseases; to name a few is arthritis, allergic inflammation, cancer, diabetes, obesity, and cystic fibrosis. Elevated CatS level is a contributing factor for related disorders, and therefore among different strategies to regulate the activity of CatS, one is to design a quality inhibitor. Earlier, we have demonstrated a highly selective CatS inhibitor, RO5444101 interacts primarily with the S2 pocket of the protein which is structurally unique in contrast to other variants of cathepsin. However, the molecular properties of RO5444101 can question its efficacy at the clinical level. In the present study, we have implemented a series of molecular modeling methods to screen the Maybridge library considering the pharmacophoric features of RO5444101 and other relevant inhibitors of CatS. Based on the priority list, eight hits were subjected to biological evaluation. Subsequently, KM07987 was found to be most potent, with the IC50 of <5 µM. Molecular dynamics simulations also relate to our experimental findings and propose the importance of CatS's S2 pocket, which primarily interacts with the inhibitors. Based on the S2 pocket interactions, structural modifications of the promising hits can further be translated into novel scaffolds for improved inhibition of CatS.

Synthesis, biological evaluation and molecular dynamic simulations of novel Benzofuran-tetrazole derivatives as potential agents against Alzheimer's disease.

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease.