Multi-cavity molecular descriptor interconnections: Enhanced protocol for prediction of serum albumin drug binding.

The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

Talazoparib Dual-targeting on Poly (ADP-ribose) Polymerase-1 and -16 Enzymes Offers a Promising Therapeutic Strategy in Small Cell Lung Cancer Therapy: Insight from Biophysical Computations.

In recent times, inhibition of poly (ADP-ribose) polymerase (PARP) enzymes by pharmacological drugs has attracted much attention as an anticancer therapy. As reported, PARP-16 has been discovered as a novel anticancer target for small cell lung cancer, and that the inhibition of both PARP-16 and PARP-1 by talazoparib can increase the overall effectiveness of talazoparib in the SCLC treatment. In this study, we employed computational approaches to investigate the differential inhibitory potency of Talazoparib on PARP-1 and PARP-16. Talazoparib has excellent PARP-1 and PARP-16 binding activities, as revealed by the ΔGbind (total binding energy). Pp16-tpb had binding energy of -34.85 kcal/mol, while pp1-tpb had a binding energy of -26.36 kcal/mol. The binding activity of Talazoparib on both PARP-1 and PARP-16 was significantly influenced by van der Waal and electrostatic interactions. Correspondingly, according to the findings of this study, binding residues with total binding energy greater than 1.00 kcal/mol contributed considerably to the Talazoparib's binding activities on PARP-1 and PARP-16. We believe the findings of this study will pave the way for developing dual targeting of PARP enzymes as a strategy for small-cell lung cancer treatment.

Simulation Models for Prediction of Bioavailability of Medicinal Drugs-the Interface Between Experiment and Computation.

The oral drug bioavailability (BA) problems have remained inevitable over the years, impairing drug efficacy and indirectly leading to eventual human morbidity and mortality. However, some conventional lab-based methods improve drug absorption leading to enhanced BA, and the recent experimental techniques are up-and-coming. Nevertheless, some have inherent drawbacks in improving the efficacy of poorly insoluble and low impermeable drugs. Drug BA and strategies to overcome these challenges were briefly highlighted. This review has significantly unravelled the different computational models for studying and predicting drug bioavailability. Several computational approaches provide mechanistic insights into the oral drug delivery system simulation of descriptors like solubility, permeability, transport protein-ligand interactions, and molecular structures. The in silico techniques have long been known still are just being applied to unravel drug bioavailability issues. Many publications have reported novel applications of the computational models towards achieving improved drug BA, including predicting gastrointestinal tract (GIT) drug absorption properties and passive intestinal membrane permeability, thus maximizing time and resources. Also, the classical molecular simulation models for free solvation energies of soluble-related processes such as solubilization, dissolutions, supersaturation, and precipitation have been used in virtual screening studies. A few of the tools are GastroPlusTM that supports biowaiver for drugs, mainly BCS class III and predicts drug compounds' absorption and pharmacokinetic process; SimCyp® simulator for mechanistic modelling and simulation of drug formulation processes; pharmacodynamics analysis on non-linear mixed-effects modelling; and mathematical models, predicting absorption potential/maximum absorption dose. This review provides in silico-experiment annexation in the drug bioavailability enhancement, possible insights that lead to critical opinion on the applications and reliability of the various in silico models as a growing tool for drug development and discovery, thus accelerating drug development processes.

Unveiling the mechanistic roles of chlorine substituted phthalazinone-based compounds containing chlorophenyl moiety towards the differential inhibition of poly (ADP-ribose) polymerase-1 in the treatment of lung cancer.

PARP-1 has become an attractive target in cancer treatment owing to its significant role in breast and ovarian cancers. The design of highly selective and effective poly (ADP ribose) polymerase-1 inhibitors has significant therapeutic advantages and has remained the core of several PARP-1-based drug discovery research. The pharmacophoric relevance of a chlorine substituent in a recent study led to the design of compounds 11c (meta-chlorophenyl) and 11d (para-chlorophenyl). In this study, we resolved the mechanistic effects of the changes in chlorine positional orientation, which underlie the inhibitory potencies and selectivity exhibited disparately by 11c and 11d. Compared to 11d, among other multiple higher-affinity complementary interactions with key site residues, the meta-Cl positioning in 11c facilitated its optimal motion and orientation towards conserved residues Arg878 and Asp766 with consistent pi-cation and pi-anion interactions, respectively, thereby favoring the stability of the ligand towards PARP-1. These could account for the higher inhibitory potency exhibited by 11c relative to 11d against PARP-1. The thermodynamics calculation revealed that 11c had a relatively higher total binding energy (ΔGbind) than 11d. We also observed that 11d displayed high deviations, compared to 11c, indicative of its unstable binding orientation. Furthermore, we reported in this study that the high involvement of electrostatic and van der Waal effects potentiated the binding affinity and strength of 11c (ΔEvdW = -50.58 and ΔEele = -27.20) relative to 11d (ΔEvdW = -49.46 and ΔEele = -19.96) at PARP-1 binding pocket. We believe the findings in this current study would provide valuable insights into the design of selective PARP-1 inhibitors containing chlorine substituent for cancer treatment, including lung cancer.Communicated by Ramaswamy H. Sarma.

Unravelling the Mechanistic Role of Quinazolinone Pharmacophore in the Inhibitory Activity of Bis-quinazolinone Derivative on Tankyrase-1 in the Treatment of Colorectal Cancer (CRC) and Non-small Cell Lung Cancer (NSCLC): A Computational Approach.

In recent years, tankyrase inhibition has gained a great focus as an anti-cancer strategy due to their modulatory effect on WNT/ß-catenin pathway implicated in many malignancies, including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Based on the structural homology in the catalytic domain of PARP enzymes, bis-quinazolinone 5 (Cpd 5) was designed to be a potent selective tankyrase inhibitor. In this study, we employed molecular dynamics simulations and binding energy analysis to decipher the underlying mechanism of TNK-1 inhibition by Cpd 5 in comparison with a known selective tankyrase, IWR-1. The Cpd 5 had a relatively higher ΔGbind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (ΔGsol) and the van der Waals energy (ΔEvdW) potentiated the affinity of Cpd 5 at TNK-1 active site. Interestingly, the keto group and the N3 atom of the quinazolinone nucleus of Cpd 5, occupying the NAM subsite, was able to form H-bond with Gly1185, thereby favoring the better stability and higher inhibitory efficacy of Cpd 5 relative to IWR-1. Our analysis proved that the firm binding of Cpd 5 was achieved by the quinazolinone groups via the hydrophobic interactions with the side chains of key site residues at the two subsite regions: His1201, Phe1188, Ala1191, and Ile1192 at the AD subsite and Tyr1224, Tyr1213, and Ala1215 at the NAM subsite. Thus, Cpd 5 is dominantly bound through π-π stacked interactions and other hydrophobic interactions. We believe that findings from this study would provide an important rationale towards the structure-based design of improved selective tankyrase inhibitors in cancer therapy.

Mechanistic Insights into the Selective Dual BET and PLK1 Inhibitory Activity of a Novel Benzamide Compound in Castration-Resistant Prostrate Cancer.

Though multifactorial, BET and PLK1 proteins have been found to be key players in the oncogenic process leading to castration-resistant prostate cancer through regulation of AR and MYC-mediated transcription. Hence, dual inhibition of these proteins appears to be an auspicious approach for CRPC therapy. WNY0824 has been reported to exhibit nanomolar range inhibition as well as significant anti-proliferative activity on AR-positive CRPC cells in vitro. However, structural, and mechanistic events associated with its dual inhibitory and anti-proliferative mechanisms remain unclear. Utilizing integrative computer-assisted atomistic techniques, analyses revealed that the dual-inhibitory activity of WNY0824 against BRD4 and PLK1 proteins is mediated by conserved residues present in the binding cavities of both proteins which are shown to elicit various strong intermolecular interactions and thus favour binding affinity. Also, binding orientation of the ligand at the protein binding cavities allowed for important hydrophobic interactions which resulted in high binding free energy of -42.50 kcal/mol and -51.64 kcal/mol towards BRD4 and PLK1, respectively. While van der Waals interactions are very important to ligand binding in BRD4-WNY complex, electrostatic interactions are pertinent to PLK1-WNY complex. Intriguingly, WNY0824 triggered conformational alterations in both proteins through increased structural instability, decreased structural compactness and mitigation in exposure of residues to solvent surface area. Consequently, critical interactions peculiar to the oncogenic activities of BRD4 and PLK1 were inhibited, a phenomenon that results in an antagonism of CRPC progression. The mechanistic insights presented in this report would further assist in the structure-based design of improved inhibitors useful in CRPC therapy.

East to West not North-West: Structure-Based Mechanistic Resolution of 8-Hydroxyl Replacement and Resulting Effects on the Activities of Imidazole-Based Heme Oxygenase-1 Inhibitors.

Upregulation of Heme Oxygenase-1 (HO-1) has been widely implicated in cancer growth and chemoresistance. This explains the numerous drug discovery efforts aimed at mitigating its pro-carcinogenic roles till date. In a recent study, two selective azole-based HO-1 inhibitors (Cpd1 and Cpd2) were synthesized, which exhibited differential inhibitory potencies of ~200µm. Interestingly, variations in the affinities of these compounds were determined by their positioning across specific regions of the HO-1 binding domain, pin-pointing a pharmacological interrelationship that remains unresolved. Therefore, in this study, using molecular dynamics simulations and binding free energy calculations, we investigate how dynamical orientations of these compounds influence their binding affinities at the active HO-1 domain. Findings revealed favorable binding for the bromobenzene and imidazole substituents of Cpd1 at the western and eastern regions of the HO-1 active domain. The constituent hydroxyl group was coordinated by residues Asp140 and Arg136 over the simulation period. On the contrary, stable binding of the bromobenzene and imidazole substituents were negated by the optimal orientations of the benzyl substituent, which extended into the northeastern region. These were supported by the displacement of Asp140 and Arg136, crucial for hydrogen bond formation in Cpd1. Also, we observed that Cpd2 exhibited high deviations indicative of an unstable binding relative to Cpd1. This further supports the presumption that Cpd2 was systematically oriented away from the active HO-1 region, a phenomenon that was due to the optimal motions of the benzyl group at the northeastern regions. The highlight of our findings is that the benzyl substituent in Cpd2 elicited negative effects on HO-1, vis a vis, instability, displacement of crucial residues, and low binding energy when compared to Cpd1. Findings pave the way for future drug discovery efforts related to HO-1 inhibition in cancer therapy.

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di-Substituted Oxadiazole-Based Dibenzo-Azepine-Dione Derivatives on Poly (ADP-Ribose) Polymerase-1.

Numerous studies have established the involvement of Poly (ADP-ribose) Polymerase-1 (PARP-1) in cancer presenting it as an important therapeutic target over recent years. Although homology among the PARP protein family makes selective targeting difficult, two compounds [d11 (0.939 µM) and d21 (0.047 µM)] with disparate inhibitory potencies against PARP-1 were recently identified. In this study, free energy calculations and molecular simulations were used to decipher underlying mechanisms of differential PARP-1 inhibition exhibited by the two compounds. The thermodynamics calculation revealed that compound d21 had a relatively higher ΔGbind than d11. High involvement of van der Waal and electrostatic effects potentiated the affinity of d21 at PARP-1 active site. More so, incorporated methyl moiety in d11 accounted for steric hindrance which, in turn, prevented complementary interactions of key site residues such as TYR889, MET890, TYR896, TYR907. Conformational studies also revealed that d21 is more stabilized for interactions in the active site compared to d11. We believe that findings from this study would provide an important avenue for the development of selective PARP-1 inhibitors.